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Bigner, Darell Doty

Overview:

The Causes, Mechanisms of Transformation and Altered Growth Control and New Therapy for Primary and Metastatic Tumors of the Central Nervous System (CNS).

There are over 100,000 deaths in the United States each year from primary brain tumors such as malignant gliomas and medulloblastomas, and metastatic tumors to the CNS and its covering from systemic tumors such as carcinoma of the lung, breast, colon, and melanoma. An estimated 43,800 cases of primary brain tumors were expected to be diagnosed last year. Of that number, approximately 3,410 diagnosed will be children less than 19 years of age. During the last 20 years, however, there has been a significant increase in survival rates for those with primary malignant brain tumors.

For the last 44 years my research has involved the investigation of the causes, mechanism of transformation and altered growth control, and development of new methods of therapy for primary brain tumors and those metastasizing to the CNS and its coverings. In collaboration with my colleagues in the Preston Robert Tisch Brain Tumor Center, new drugs and those not previously thought to be active against CNS tumors have been identified. Overcoming mechanisms of drug resistance in primary brain tumors are also being pursued.

As Director of the Preston Robert Tisch Brain Tumor Center and the Pediatric Brain Tumor Foundation Institute at Duke and Leader of the Neuro-Oncology Program of the Duke Comprehensive Cancer Center, I coordinate the research activities of all 37 faculty members in the Brain Tumor Center and Neuro-Oncology Program. These faculty members have projects ranging from very basic research into molecular etiology, molecular epidemiology, signal transduction; translational research performing pre-clinical evaluation of new therapies, and many clinical investigative efforts. I can describe any of the Brain Tumor Center faculty member’s research to third year students and then direct them to specific faculty members with whom the students would like a discussion.

My personal research over the last 25 years has focused on molecularly targeted therapy of primary and metastatic CNS tumors with monoclonal antibodies and their fragments. Our most advanced study is with a molecule we discovered many years ago, the extracellular matrix molecule, Tenascin. We have treated over 150 malignant brain tumor patients with excellent results with a radiolabeled antibody we developed against Tenascin. We currently have a Food and Drug Administration Investigational New Drug Permit for an immunotoxin composed of a single fragment chain antibody fragment genetically conjugated to Pseudomonas toxin. The targeted molecule is a constitutively active mutant of the wild type epidermal growth factor receptor that we call EGFRvIII, which has a tumor-specific epitope. This immunotoxin is being administered by catheters and slow infusion directly around the resection cavity of malignant gliomas. The first trial is a Phase I safety, efficacy, and dose escalation trial. I have just published, in the Journal of Clinical Oncology, a promising vaccine trial for glioblastoma with intradermal injections of a peptide of EGFRvIII.

We have identified through genome-wide screening methodology several new target molecules selectively expressed on malignant brain tumors, but not on normal brain. These include glycoprotein non-metastatic B (GPNMB), a molecule shared with malignant melanoma; MRP3, a member of the multidrug resistant family; and two lacto series gangliosides, 3'-isoLM1 and 3',6'-isoLD1 and chondroitin proteoglycan sulfate, which are heavily expressed in developing brain but are only re-expressed on malignant brain tumors with no expression on normal adult brain. We are raising conventional monoclonal antibodies against all of these targets as well as developing single fragment chain molecules from naïve human libraries. When necessary, affinity maturation in vitro is carried out and the antibodies and fragments are armed either with radioactive iodine, radioactive lutetium, or radioactive Astatine-211. Other constructs are evaluated for unarmed activity and some are armed with Pseudomonas exotoxin. After development of the constructs, they are evaluated in human malignant glioma xenograft systems and then all studies necessary for Investigational New Drug Permits from the Food and Drug Administration are carried out prior to actual clinical trial.

I was senior author on a New England Journal of Medicine paper that was the first to show markedly increased survival in low to intermediate grade gliomas with an isocitrate dehydrogenase mutation.

The first fully funded Specialized Research Center on Primary and Metastatic Tumors to the CNS funded by the National Institutes of Health, of which I am Principal Investigator, is currently in its 27th year of continuous funding. My NCI MERIT Award, which ranked in the upper 1.2 percentile of all NIH grants at the time of its last review, is currently in its 40th year of continuous funding. It is one of the few MERIT awards awarded three consecutive times, and it is the longest continually funded grant of the NCI Division of Cancer Diagnosis and Treatment. I am the Director of the Pediatric Brain Tumor Foundation Institute at Duke, which was established in 2003 and is supported by a $12 million grant from the Foundation for research on childhood brain tumors.

In addition to the representative publications listed, I have made national presentations and international presentations during the past year.

My laboratory has trained over 50 third year medical students, residents, Ph.D. students, and postdoctoral fellows and I have a great deal of experience in career development with some students having advanced all the way from fellowship status to endowed professorships. A major goal with third year medical students is to perform work that can be presented in abstract form at national or international meetings and to obtain publication in major peer-reviewed journals.

Positions:

E. L. and Lucille F. Jones Cancer Research Professor, in the School of Medicine

Pathology
School of Medicine

Professor of Pathology

Pathology
School of Medicine

Professor of Surgery

Surgery
School of Medicine

Professor of Neurosurgery

Neurosurgery
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Chief, Division of Experimental Pathology

Pathology
School of Medicine

Education:

M.D. 1965

M.D. — Duke University

Ph.D. 1971

Ph.D. — Duke University

Intern, Surgery

Duke University

Fellow, Neurological Surgery

Duke University

Clinical Associate, Medical Neurology

National Institutes of Health

News:

Grants:

Oncolytic Polovirus, Immunotoxin, and Checkpoint Inhibitor Therapy of Gliomas

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 01, 2015
End Date
July 31, 2022

Translational Research in Surgical Oncology

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
January 01, 2002
End Date
August 31, 2021

Regional Oncolytic Poliovirus Immunotherapy for Breast Cancer

Administered By
Surgery, Surgical Sciences
AwardedBy
Department of Defense
Role
Collaborator
Start Date
August 01, 2016
End Date
July 31, 2021

Organization and Function of Cellular Structure

Administered By
Basic Science Departments
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1975
End Date
June 30, 2020

The Role of IDH1 Mutations in Gliomagenesis and Metabolism

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
July 01, 2009
End Date
March 31, 2020

NINDS Research Education Programs for Residents and Fellows in Neurosurgery

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
March 01, 2009
End Date
June 30, 2019

Systemic EGFRvIII-targeted bispecific antibody as immunotherapy for glioblastoma

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
March 01, 2015
End Date
February 28, 2019

Targeting Translation Control in Malignant Glioma

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
January 17, 2007
End Date
May 31, 2018

Phase-1 clinical trial of PVSRIPO oncolytic immunotherapy in pediatric HGG

Administered By
Neurosurgery
AwardedBy
Solving Kids' Cancer
Role
Co Investigator
Start Date
April 01, 2016
End Date
March 31, 2018

A Genetically Modified Poliovirus and Immunotoxin for Malignant Brain Tumors

Administered By
Pathology
AwardedBy
Brain Tumor Research Charity
Role
Principal Investigator
Start Date
December 30, 2013
End Date
December 29, 2017

Determining the maximum tolerated dose of a recombinant immunotoxin targeting wildtype EGFR and Mutant EGFRvIII

Administered By
Pathology
AwardedBy
Uncle Kory Foundation
Role
Principal Investigator
Start Date
November 01, 2016
End Date
October 31, 2017

Oncolytic PVSRIPO Expressing Tumor Antigens as a Cancer Vaccine

Administered By
Neurosurgery
AwardedBy
Oligo Nation
Role
Significant Contributor
Start Date
September 15, 2016
End Date
September 05, 2017

Enhancing dendritic cell migration to drive potent anti-tumor immune responses

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 2013
End Date
June 30, 2017

Vaccine Immunotoxin and Radioimmunotherapy of Primary and Metastatic CNS Tumors

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 11, 2012
End Date
June 30, 2017

Immunosequencing of poliovirus and immunotoxin treated brain tumor samples

Administered By
Pathology
AwardedBy
Uncle Kory Foundation
Role
Principal Investigator
Start Date
December 01, 2015
End Date
November 30, 2016

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
July 01, 1998
End Date
August 31, 2016

Oncolytic Poliovirus Immunotherapy of Malignant Glioma

Administered By
Pathology
AwardedBy
The Slomo and Cindy Silvian Foundation, Inc
Role
Principal Investigator
Start Date
December 12, 2014
End Date
December 11, 2015

Clinical Oncology Research Career Development Program

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 29, 2009
End Date
July 31, 2015

Oncolytic Virotherapy of Meningeal Cancer

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
July 01, 2009
End Date
May 31, 2015

SRC on Primary Tumors of the CNS

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 1999
End Date
January 31, 2015

Adoptive Immunotherapy for GBM During Hematopoietic Recovery from Temozolomide

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 23, 2009
End Date
July 31, 2014

Targeting EGFRvIII in Brain Tumors with Bispecific Antibodies

Administered By
School of Medicine
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
May 01, 2013
End Date
April 30, 2014

Modulation of the blood-tumor barrier through targeted suppression of claudin 5

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
August 16, 2011
End Date
August 02, 2013

Reversal of CMV-specific immune deficits in patients with glioblastoma

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
September 15, 2009
End Date
June 30, 2013

Brain Tumors - Immunological and Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 20, 2001
End Date
March 31, 2013

NCI Howard Temin Award (K01) Transition

Administered By
Surgery, Surgical Sciences
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 25, 2006
End Date
July 31, 2012

Pre-clinical Translation of Regulatory T-cell Inhibition in Brain Tumors

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
July 01, 2010
End Date
June 30, 2012

The Role of OTX2 in Molecular Pathogenesis of Medulloblastoma

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
July 01, 2006
End Date
May 31, 2012

Small Animal PET / CT Molecular Imaging

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Major User
Start Date
April 01, 2011
End Date
March 31, 2012

Meningioma: Risk Factors and Quality of Life

Administered By
Duke Cancer Institute
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
June 26, 2006
End Date
March 31, 2012

SPORE in Brain Cancer

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2004
End Date
August 31, 2011

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 15, 2005
End Date
August 31, 2010

Temodar Resistance in CNS Tumors

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
June 22, 1992
End Date
April 30, 2010

Innovative Assays for Oncogenic Hedgehog Signaling

Administered By
Medicine, Gastroenterology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
April 21, 2006
End Date
February 28, 2010

Stem Cell-Like Glioma Cells in Angiogenesis

Administered By
Neurology, General & Community Neurology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
April 07, 2008
End Date
January 31, 2009

TGFbeta-PTEN Interactions in Glioma Biology & Therapy

Administered By
Neurology, General & Community Neurology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
August 01, 2006
End Date
September 30, 2008

Molecular Mechanisms of SPARC Mediated Glioma Invasion

Administered By
Neurology, General & Community Neurology
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
February 15, 2006
End Date
September 30, 2008

Phase II Study of 44Gy from 131I-81C6 for CNS Tumors

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 29, 2003
End Date
August 31, 2006

High-Resolution CGH Characterization of Brain Tumors

Administered By
Duke Molecular Physiology Institute
AwardedBy
National Institutes of Health
Role
Consultant
Start Date
April 15, 2004
End Date
July 31, 2006

Regional AGT Depletion of CNS and Leptomeningeal Tumors

Administered By
Neurosurgery, Neuro-Oncology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
February 01, 2002
End Date
January 31, 2006

Anti-Tenascin Antibody Constructs

Administered By
Radiology
AwardedBy
Department of Energy
Role
Co Investigator
Start Date
May 01, 1995
End Date
November 30, 2005

GCRC CAP

Administered By
Neurosurgery
AwardedBy
National Institutes of Health
Role
Mentor
Start Date
September 01, 2000
End Date
August 31, 2005

Therapy of Temodar plus O6-BG in Malignant Glioma

Administered By
Neurology, General & Community Neurology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 01, 2003
End Date
March 31, 2005

SPORE in Brain Cancer

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 30, 2002
End Date
August 31, 2004

Administrative Supplement: SRC on Primary and Metastatic Tumors of the CNS\

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 2001
End Date
January 31, 2004

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1999
End Date
January 31, 2004

ZD1839 Therapy of Glioblastoma Multiforme

Administered By
Pediatrics
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
April 01, 2001
End Date
March 31, 2003

Development of Novel Tumor Imaging Agents

Administered By
Radiology
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
March 07, 2000
End Date
February 28, 2003

The Role Of Tgfb In Brain Tumors

Administered By
Neurology, General & Community Neurology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
July 01, 1998
End Date
June 30, 2001

Temozolomide Resistance in CNS Tumors

Administered By
Pediatrics
AwardedBy
National Institutes of Health
Role
Collaborator
Start Date
April 01, 1999
End Date
March 31, 2001

Brain Tumors--Immunological and Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
December 01, 1976
End Date
March 31, 2001

SRC on Primary and Metastatic Tumors of the CNS

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
February 01, 2000
End Date
January 31, 2001

Administrative Supplement to NS20023 (SPS ID19857)

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 1999
End Date
January 31, 2000

Brain Tumors - Immunological And Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1997
End Date
March 31, 1999

Src On Primary And Matastatic Tumors Of The Cns

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 1994
End Date
March 31, 1999

Astatine And Iodine Radiolabeled Monoclonal Antibodies

Administered By
Radiology, Nuclear Medicine
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
April 01, 1994
End Date
March 31, 1999

Src On Primary And Metastatic Tumors Of The Cns

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
March 01, 1997
End Date
February 28, 1999

Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Comprehensive Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Comprehensive Cancer Center Core Support Grant

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co-Principal Investigator
Start Date
September 01, 1976
End Date
December 31, 1998

Research Training In Neuro-Oncology

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1987
End Date
June 30, 1998

Research Training In Neurology-Oncology

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1992
End Date
June 30, 1997

Brain Tumors -- Immunological And Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1994
End Date
March 31, 1996

Brain Tumors: Immunological And Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1993
End Date
March 31, 1996

Intrathecal Therapy Of Melanoma Neoplastic Meningitis

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
May 01, 1993
End Date
April 30, 1995

Src On Malignant Human Gliomas And Medulloblastomas

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1993
End Date
March 31, 1994

Src On Malignant Human Gliomas And Medulloblastomas

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1992
End Date
March 31, 1994

Src On Malignant Human Gliomas And Medulloblastoma

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1989
End Date
March 01, 1994

Brain Tumors: Immunological And Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1992
End Date
March 31, 1993

Brain Tumors; Immunological And Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1990
End Date
March 31, 1993

Brain Tumor: Immunological And Biological Studies

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1988
End Date
March 01, 1993

Malignant Human Gliomas And Medulloblastoma

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1987
End Date
March 01, 1989

Malignant Human Gliomas And Medulloblastoma

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
April 01, 1985
End Date
March 01, 1989

Sixth International Conference On Brain Tumor Research A

Administered By
Pathology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1985
End Date
June 01, 1986
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Awards:

Basic Science Lecture Award. American Society of Cytopathology.

Type
National
Awarded By
American Society of Cytopathology
Date
January 01, 1991

Publications:

Development and validation of a cell-based fluorescent method for measuring antibody affinity.

Monoclonal antibodies have become essential tools for diagnostic and therapeutic purposes. Antibody affinity is one of the critical factors influencing the therapeutic success of tumor-targeting antibodies. Therefore, developing an accurate and reliable method for determining antibody affinity is crucial. In this study, we describe a fluorescent cell-based immunosorbent assay that can accurately measure antibody affinity (KD) in the nanomolar range. This method involves the addition of fluorescently labeled antibodies to antigen-positive and antigen-negative cell lines fixed on 96-well plates. The fluorescent signals from nonspecific binding to negative control cell lines is subtracted from the specific binding to the antigen-positive cell lines. The KD values obtained by this method were comparable with values obtained by the flow cytometry and radioactive (I125) scatchard assay. Our results demonstrate that this modified cell-based fluorescent method allows for a convenient and efficient identification of therapeutically relevant leads.

Authors
Yu, X; Pegram, CN; Bigner, DD; Chandramohan, V
MLA Citation
Yu, X, Pegram, CN, Bigner, DD, and Chandramohan, V. "Development and validation of a cell-based fluorescent method for measuring antibody affinity." Journal of immunological methods 442 (March 2017): 49-53.
PMID
28024998
Source
epmc
Published In
Journal of Immunological Methods
Volume
442
Publish Date
2017
Start Page
49
End Page
53
DOI
10.1016/j.jim.2016.12.004

Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression.

IDH1 mutations occur in the majority of low-grade gliomas and lead to the production of the oncometabolite, D-2-hydroxyglutarate (D-2HG). To understand the effects of tumor-associated mutant IDH1 (IDH1-R132H) on both the neural stem cell (NSC) population and brain tumorigenesis, genetically faithful cell lines and mouse model systems were generated. Here, it is reported that mouse NSCs expressing Idh1-R132H displayed reduced proliferation due to p53-mediated cell cycle arrest as well as a decreased ability to undergo neuronal differentiation. In vivo, Idh1-R132H expression reduced proliferation of cells within the germinal zone of the subventricular zone (SVZ). The NSCs within this area were dispersed and disorganized in mutant animals, suggesting that Idh1-R132H perturbed the NSCs and the microenvironment from which gliomas arise. Additionally, tumor-bearing animals expressing mutant Idh1 displayed a prolonged survival and also overexpressed Olig2, features consistent with IDH1-mutated human gliomas. These data indicate that mutant Idh1 disrupts the NSC microenvironment and the candidate cell of origin for glioma; thus, altering the progression of tumorigenesis. Additionally, this study provides a mutant Idh1 brain tumor model that genetically recapitulates human disease, laying the foundation for future investigations on mutant IDH1-mediated brain tumorigenesis and targeted therapy.Through the use of a conditional mutant mouse model that confers a less aggressive tumor phenotype, this study reveals that mutant Idh1 impacts the candidate cell of origin for gliomas.

Authors
Pirozzi, CJ; Carpenter, AB; Waitkus, MS; Wang, CY; Zhu, H; Hansen, LJ; Chen, LH; Greer, PK; Feng, J; Wang, Y; Bock, CB; Fan, P; Spasojevic, I; McLendon, RE; Bigner, DD; He, Y; Yan, H
MLA Citation
Pirozzi, CJ, Carpenter, AB, Waitkus, MS, Wang, CY, Zhu, H, Hansen, LJ, Chen, LH, Greer, PK, Feng, J, Wang, Y, Bock, CB, Fan, P, Spasojevic, I, McLendon, RE, Bigner, DD, He, Y, and Yan, H. "Mutant IDH1 Disrupts the Mouse Subventricular Zone and Alters Brain Tumor Progression." Molecular cancer research : MCR (February 2017).
PMID
28148827
Source
epmc
Published In
Molecular cancer research : MCR
Publish Date
2017
DOI
10.1158/1541-7786.mcr-16-0485

Immunotoxin Therapy for Lung Cancer.

Authors
Xie, L-Y; Piao, H-L; Fan, M; Zhang, Z; Wang, C; Bigner, DD; Bao, X-H
MLA Citation
Xie, L-Y, Piao, H-L, Fan, M, Zhang, Z, Wang, C, Bigner, DD, and Bao, X-H. "Immunotoxin Therapy for Lung Cancer." Chinese medical journal 130.5 (January 2017): 607-612.
PMID
28229994
Source
epmc
Published In
Chinese medical journal
Volume
130
Issue
5
Publish Date
2017
Start Page
607
End Page
612
DOI
10.4103/0366-6999.200540

Production and quality control assessment of a GLP-grade immunotoxin, D2C7-(scdsFv)-PE38KDEL, for a phase I/II clinical trial.

D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel recombinant Pseudomonas exotoxin A-based immunotoxin (IT), targeting both wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins overexpressed in glioblastomas. Initial pre-clinical testing demonstrated the anti-tumor efficacy of D2C7-IT against orthotopic glioblastoma xenograft models expressing EGFRwt, EGFRvIII, or both EGFRwt and EGFRvIII. A good laboratory practice (GLP) manufacturing process was developed to produce sufficient material for a phase I/II clinical trial. D2C7-IT was expressed under the control of the T7 promoter in Escherichia coli BLR (λ DE3). D2C7-IT was produced by a 10-L batch fermentation process and was then purified from inclusion bodies using anion exchange, size exclusion, and an endotoxin removal process that achieved a yield of over 300 mg of purified protein. The final vialed batch of D2C7-IT for clinical testing was at a concentration of 0.12 ± 0.1 mg/mL, the pH was at 7.4 ± 0.4, and endotoxin levels were below the detection limit of 10 EU/mL (1.26 EU/mL). The stability of the vialed D2C7-IT has been monitored over a period of 42 months through protein concentration, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), isoelectric focusing, size exclusion chromatography, cytotoxicity, sterility, and pH measurements. The vialed D2C7-IT is currently being tested in a phase I/II clinical trial by intratumoral convection-enhanced delivery for 72 h in patients with recurrent glioblastoma (NCT02303678, D2C7 for Adult Patients with Recurrent Malignant Glioma; clinicaltrials.gov ).

Authors
Chandramohan, V; Pegram, CN; Piao, H; Szafranski, SE; Kuan, C-T; Pastan, IH; Bigner, DD
MLA Citation
Chandramohan, V, Pegram, CN, Piao, H, Szafranski, SE, Kuan, C-T, Pastan, IH, and Bigner, DD. "Production and quality control assessment of a GLP-grade immunotoxin, D2C7-(scdsFv)-PE38KDEL, for a phase I/II clinical trial." Applied microbiology and biotechnology (December 24, 2016).
PMID
28013405
Source
epmc
Published In
Applied Microbiology and Biotechnology
Publish Date
2016
DOI
10.1007/s00253-016-8063-x

Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models.

Intratumoral inoculation of viruses with tumor-selective cytotoxicity may induce cancer cell death and, thereby, shrink neoplastic lesions. It is unlikely, however, that viral tumor cell killing alone could produce meaningful, durable clinical responses, as clinically suitable 'oncolytic' viruses are severely attenuated and their spread and propagation are opposed by host immunity. Thus, a more propitious event in this context is the innate antiviral response to intratumoral virus administration, in particular for recruiting durable adaptive immune effector responses. It may represent a double-edged sword, as innate immune activation may eliminate infected tumor cells early, intercept viral spread and block any meaningful therapeutic response. The innate response to viral infection of tumors may be very different from that in non-malignant target tissues, owing to the unusual composition/tissue properties of tumor stroma. In this work, we report investigations of the innate immune response to the oncolytic poliovirus recombinant, PVSRIPO, in two mouse xenotransplantation models for breast and prostate cancer. Our observations indicate short-term virus persistence in infected tumors and virus recovery indicative of modest intratumoral propagation and persistence. Yet, a powerful innate inflammatory response coincided with chemokine induction and myeloid cell infiltration into tumors that was, interestingly, dominated by neutrophils. The combined effect of PVSRIPO tumor infection and the innate response it elicits was significant tumor regression in both models.

Authors
Holl, EK; Brown, MC; Boczkowski, D; McNamara, MA; George, DJ; Bigner, DD; Gromeier, M; Nair, SK
MLA Citation
Holl, EK, Brown, MC, Boczkowski, D, McNamara, MA, George, DJ, Bigner, DD, Gromeier, M, and Nair, SK. "Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models." Oncotarget 7.48 (November 2016): 79828-79841.
PMID
27806313
Source
epmc
Published In
Oncotarget
Volume
7
Issue
48
Publish Date
2016
Start Page
79828
End Page
79841
DOI
10.18632/oncotarget.12975

POLIO VIRUS THERAPY HAS IMMUNOSTIMULATORY PROPERTIES THAT ARE ACTIVE AGAINST SOLID TUMORS

Authors
Holl, E; Brown, M; Boczkowski, D; Bigner, D; Gromeier, M; Nair, S
MLA Citation
Holl, E, Brown, M, Boczkowski, D, Bigner, D, Gromeier, M, and Nair, S. "POLIO VIRUS THERAPY HAS IMMUNOSTIMULATORY PROPERTIES THAT ARE ACTIVE AGAINST SOLID TUMORS." November 2016.
Source
wos-lite
Published In
Cytokine
Volume
87
Publish Date
2016
Start Page
61
End Page
62

Rapid Reprogramming of Primary Human Astrocytes into Potent Tumor-Initiating Cells with Defined Genetic Factors.

Cancer stem-like cells (CSC) are thought to drive brain cancer, but their cellular and molecular origins remain uncertain. Here, we report the successful generation of induced CSC (iCSC) from primary human astrocytes through the expression of defined genetic factors. Combined transduction of four factors, Myc, Oct-4, p53DD, and Ras, induced efficient transformation of primary human astrocytes into malignant cells with powerful tumor-initiating capabilities. Notably, transplantation of 100 transduced cells into nude mice was sufficient for tumor formation. The cells showed unlimited self-renewal ability with robust telomerase activities. In addition, they expressed typical glioma stem-like cell markers, such as CD133, CD15, and CD90. Moreover, these cells could form spheres in culture and differentiate into neuron-like, astrocyte-like, and oligodendrocyte-like cells. Finally, they also displayed resistance to the widely used brain cancer drug temozolomide. These iCSCs could provide important tools for studies of glioma biology and therapeutics development. Cancer Res; 76(17); 5143-50. ©2016 AACR.

Authors
Li, F; Liu, X; Sampson, JH; Bigner, DD; Li, C-Y
MLA Citation
Li, F, Liu, X, Sampson, JH, Bigner, DD, and Li, C-Y. "Rapid Reprogramming of Primary Human Astrocytes into Potent Tumor-Initiating Cells with Defined Genetic Factors." Cancer research 76.17 (September 2016): 5143-5150.
PMID
27364552
Source
epmc
Published In
Cancer Research
Volume
76
Issue
17
Publish Date
2016
Start Page
5143
End Page
5150
DOI
10.1158/0008-5472.can-16-0171

IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma.

Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity and overall mortality. Through the comparison of cytokines and growth factors in the cerebrospinal fluid (CSF) of metastatic medulloblastoma patients with factors also in conditioned media of metastatic MYC amplified medulloblastoma or leptomeningeal cells, we were led to explore the bioactivity of IGF1 in medulloblastoma by elevated CSF levels of IGF1, IGF-sequestering IGFBP3, IGFBP3-cleaving proteases (MMP and tPA), and protease modulators (TIMP1 and PAI-1). IGF1 led not only to receptor phosphorylation but also accelerated migration/adhesion in MYC amplified medulloblastoma cells in the context of appropriate matrix or meningothelial cells. Clinical correlation suggests a peri-/sub-meningothelial source of IGF-liberating proteases that could facilitate leptomeningeal metastasis. In parallel, studies of key factors responsible for cell autonomous growth in MYC amplified medulloblastoma prioritized IGF1R inhibitors. Together, our studies identify IGF1R as a high value target for clinical trials in high risk medulloblastoma.

Authors
Svalina, MN; Kikuchi, K; Abraham, J; Lal, S; Davare, MA; Settelmeyer, TP; Young, MC; Peckham, JL; Cho, Y-J; Michalek, JE; Hernandez, BS; Berlow, NE; Jackson, M; Guillaume, DJ; Selden, NR; Bigner, DD; Nazemi, KJ; Green, SC; Corless, CL; Gultekin, S; Mansoor, A; Rubin, BP; Woltjer, R; Keller, C
MLA Citation
Svalina, MN, Kikuchi, K, Abraham, J, Lal, S, Davare, MA, Settelmeyer, TP, Young, MC, Peckham, JL, Cho, Y-J, Michalek, JE, Hernandez, BS, Berlow, NE, Jackson, M, Guillaume, DJ, Selden, NR, Bigner, DD, Nazemi, KJ, Green, SC, Corless, CL, Gultekin, S, Mansoor, A, Rubin, BP, Woltjer, R, and Keller, C. "IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma." June 3, 2016.
PMID
27255663
Source
epmc
Published In
Scientific Reports
Volume
6
Publish Date
2016
Start Page
27012
DOI
10.1038/srep27012

IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma

Authors
Svalina, MN; Kikuchi, K; Abraham, J; Lal, S; Davare, MA; Settelmeyer, TP; Young, MC; Peckham, JL; Cho, Y-J; Michalek, JE; Hernandez, BS; Berlow, NE; Jackson, M; Guillaume, DJ; Selden, NR; Bigner, DD; Nazemi, KJ; Green, SC; Corless, CL; Gultekin, S; Mansoor, A; Rubin, BP; Woltjer, R; Keller, C
MLA Citation
Svalina, MN, Kikuchi, K, Abraham, J, Lal, S, Davare, MA, Settelmeyer, TP, Young, MC, Peckham, JL, Cho, Y-J, Michalek, JE, Hernandez, BS, Berlow, NE, Jackson, M, Guillaume, DJ, Selden, NR, Bigner, DD, Nazemi, KJ, Green, SC, Corless, CL, Gultekin, S, Mansoor, A, Rubin, BP, Woltjer, R, and Keller, C. "IGF1R as a Key Target in High Risk, Metastatic Medulloblastoma." SCIENTIFIC REPORTS 6 (June 3, 2016).
Source
wos-lite
Published In
Scientific Reports
Volume
6
Publish Date
2016
DOI
10.1038/srep27012

Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats.

D2C7-(scdsFv)-PE38KDEL (D2C7-IT) is a novel immunotoxin that reacts with wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFRvIII proteins overexpressed in glioblastomas. This study assessed the toxicity of intracerebral administration of D2C7-IT to support an initial Food and Drug Administration Investigational New Drug application. After the optimization of the formulation and administration, two cohorts (an acute and chronic cohort necropsied on study days 5 and 34) of Sprague-Dawley (SD) rats (four groups of 5 males and 5 females) were infused with the D2C7-IT formulation at total doses of 0, 0.05, 0.1, 0.4 μg (the acute cohort) and 0, 0.05, 0.1, 0.35 μg (the chronic cohort) for approximately 72 h by intracerebral convection-enhanced delivery using osmotic pumps. Mortality was observed in the 0.40 μg (5/10 rats) and 0.35 μg (4/10 rats) high-dose groups of each cohort. Body weight loss and abnormal behavior were only revealed in the rats treated with high doses of D2C7-IT. No dose-related effects were observed in clinical laboratory tests in either cohort. A gross pathologic examination of systemic tissues from the high-dose and control groups in both cohorts exhibited no dose-related or drug-related pathologic findings. Brain histopathology revealed the frequent occurrence of dose-related encephalomalacia, edema, and demyelination in the high-dose groups of both cohorts. In this study, the maximum tolerated dose of D2C7-IT was determined to be between 0.10 and 0.35 μg, and the no-observed-adverse-effect-level was 0.05 μg in SD rats. Both parameters were utilized to design the Phase I/II D2C7-IT clinical trial.

Authors
Bao, X; Chandramohan, V; Reynolds, RP; Norton, JN; Wetsel, WC; Rodriguiz, RM; Aryal, DK; McLendon, RE; Levin, ED; Petry, NA; Zalutsky, MR; Burnett, BK; Kuan, C-T; Pastan, IH; Bigner, DD
MLA Citation
Bao, X, Chandramohan, V, Reynolds, RP, Norton, JN, Wetsel, WC, Rodriguiz, RM, Aryal, DK, McLendon, RE, Levin, ED, Petry, NA, Zalutsky, MR, Burnett, BK, Kuan, C-T, Pastan, IH, and Bigner, DD. "Preclinical toxicity evaluation of a novel immunotoxin, D2C7-(scdsFv)-PE38KDEL, administered via intracerebral convection-enhanced delivery in rats." Investigational new drugs 34.2 (April 2016): 149-158.
PMID
26728879
Source
epmc
Published In
Investigational New Drugs
Volume
34
Issue
2
Publish Date
2016
Start Page
149
End Page
158
DOI
10.1007/s10637-015-0318-3

Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis.

Patients with incomplete surgical resection of medulloblastoma are controversially regarded as having a marker of high-risk disease, which leads to patients undergoing aggressive surgical resections, so-called second-look surgeries, and intensified chemoradiotherapy. All previous studies assessing the clinical importance of extent of resection have not accounted for molecular subgroup. We analysed the prognostic value of extent of resection in a subgroup-specific manner.We retrospectively identified patients who had a histological diagnosis of medulloblastoma and complete data about extent of resection and survival from centres participating in the Medulloblastoma Advanced Genomics International Consortium. We collected from resections done between April, 1997, and February, 2013, at 35 international institutions. We established medulloblastoma subgroup affiliation by gene expression profiling on frozen or formalin-fixed paraffin-embedded tissues. We classified extent of resection on the basis of postoperative imaging as gross total resection (no residual tumour), near-total resection (<1·5 cm(2) tumour remaining), or sub-total resection (≥1·5 cm(2) tumour remaining). We did multivariable analyses of overall survival and progression-free survival using the variables molecular subgroup (WNT, SHH, group 4, and group 3), age (<3 vs ≥3 years old), metastatic status (metastases vs no metastases), geographical location of therapy (North America/Australia vs rest of the world), receipt of chemotherapy (yes vs no) and receipt of craniospinal irradiation (<30 Gy or >30 Gy vs no craniospinal irradiation). The primary analysis outcome was the effect of extent of resection by molecular subgroup and the effects of other clinical variables on overall and progression-free survival.We included 787 patients with medulloblastoma (86 with WNT tumours, 242 with SHH tumours, 163 with group 3 tumours, and 296 with group 4 tumours) in our multivariable Cox models of progression-free and overall survival. We found that the prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. We identified a progression-free survival benefit for gross total resection over sub-total resection (hazard ratio [HR] 1·45, 95% CI 1·07-1·96, p=0·16) but no overall survival benefit (HR 1·23, 0·87-1·72, p=0·24). We saw no progression-free survival or overall survival benefit for gross total resection compared with near-total resection (HR 1·05, 0·71-1·53, p=0·8158 for progression-free survival and HR 1·14, 0·75-1·72, p=0·55 for overall survival). No significant survival benefit existed for greater extent of resection for patients with WNT, SHH, or group 3 tumours (HR 1·03, 0·67-1·58, p=0·89 for sub-total resection vs gross total resection). For patients with group 4 tumours, gross total resection conferred a benefit to progression-free survival compared with sub-total resection (HR 1·97, 1·22-3·17, p=0·0056), especially for those with metastatic disease (HR 2·22, 1·00-4·93, p=0·050). However, gross total resection had no effect on overall survival compared with sub-total resection in patients with group 4 tumours (HR 1·67, 0·93-2·99, p=0·084).The prognostic benefit of increased extent of resection for patients with medulloblastoma is attenuated after molecular subgroup affiliation is taken into account. Although maximum safe surgical resection should remain the standard of care, surgical removal of small residual portions of medulloblastoma is not recommended when the likelihood of neurological morbidity is high because there is no definitive benefit to gross total resection compared with near-total resection.Canadian Cancer Society Research Institute, Terry Fox Research Institute, Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, and the Garron Family Chair in Childhood Cancer Research.

Authors
Thompson, EM; Hielscher, T; Bouffet, E; Remke, M; Luu, B; Gururangan, S; McLendon, RE; Bigner, DD; Lipp, ES; Perreault, S; Cho, Y-J; Grant, G; Kim, S-K; Lee, JY; Rao, AAN; Giannini, C; Li, KKW; Ng, H-K; Yao, Y; Kumabe, T; Tominaga, T; Grajkowska, WA; Perek-Polnik, M; Low, DCY; Seow, WT; Chang, KTE; Mora, J; Pollack, IF; Hamilton, RL; Leary, S; Moore, AS; Ingram, WJ; Hallahan, AR; Jouvet, A; Fèvre-Montange, M; Vasiljevic, A; Faure-Conter, C; Shofuda, T; Kagawa, N; Hashimoto, N; Jabado, N et al.
MLA Citation
Thompson, EM, Hielscher, T, Bouffet, E, Remke, M, Luu, B, Gururangan, S, McLendon, RE, Bigner, DD, Lipp, ES, Perreault, S, Cho, Y-J, Grant, G, Kim, S-K, Lee, JY, Rao, AAN, Giannini, C, Li, KKW, Ng, H-K, Yao, Y, Kumabe, T, Tominaga, T, Grajkowska, WA, Perek-Polnik, M, Low, DCY, Seow, WT, Chang, KTE, Mora, J, Pollack, IF, Hamilton, RL, Leary, S, Moore, AS, Ingram, WJ, Hallahan, AR, Jouvet, A, Fèvre-Montange, M, Vasiljevic, A, Faure-Conter, C, Shofuda, T, Kagawa, N, Hashimoto, N, and Jabado, N et al. "Prognostic value of medulloblastoma extent of resection after accounting for molecular subgroup: a retrospective integrated clinical and molecular analysis." The Lancet. Oncology 17.4 (April 2016): 484-495.
PMID
26976201
Source
epmc
Published In
The Lancet Oncology
Volume
17
Issue
4
Publish Date
2016
Start Page
484
End Page
495
DOI
10.1016/s1470-2045(15)00581-1

CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains.

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults with a 5-year overall survival rate of less than 10%. Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, expressed in the lymphatic endothelium. Several solid tumors overexpress PDPN, including the mesenchymal type of GBM, which has been reported to present the worst prognosis among GBM subtypes. Chimeric antigen receptor (CAR)-transduced T cells can recognize predefined tumor surface antigens independent of MHC restriction, which is often downregulated in gliomas. We constructed a lentiviral vector expressing a third-generation CAR comprising a PDPN-specific antibody (NZ-1-based single-chain variable fragment) with CD28, 4-1BB, and CD3ζ intracellular domains. CAR-transduced peripheral blood monocytes were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. CAR T-cell therapy that targets PDPN would be a promising adoptive immunotherapy to treat mesenchymal GBM.

Authors
Shiina, S; Ohno, M; Ohka, F; Kuramitsu, S; Yamamichi, A; Kato, A; Motomura, K; Tanahashi, K; Yamamoto, T; Watanabe, R; Ito, I; Senga, T; Hamaguchi, M; Wakabayashi, T; Kaneko, MK; Kato, Y; Chandramohan, V; Bigner, DD; Natsume, A
MLA Citation
Shiina, S, Ohno, M, Ohka, F, Kuramitsu, S, Yamamichi, A, Kato, A, Motomura, K, Tanahashi, K, Yamamoto, T, Watanabe, R, Ito, I, Senga, T, Hamaguchi, M, Wakabayashi, T, Kaneko, MK, Kato, Y, Chandramohan, V, Bigner, DD, and Natsume, A. "CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains." Cancer immunology research 4.3 (March 2016): 259-268.
PMID
26822025
Source
epmc
Published In
Cancer Immunology Research
Volume
4
Issue
3
Publish Date
2016
Start Page
259
End Page
268
DOI
10.1158/2326-6066.cir-15-0060

MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B.

The hypoxic tumor microenvironment serves as a niche for maintaining the glioma-initiating cells (GICs) that are critical for glioblastoma (GBM) occurrence and recurrence. Here, we report that hypoxia-induced miR-215 is vital for reprograming GICs to fit the hypoxic microenvironment via suppressing the expression of an epigenetic regulator KDM1B and modulating activities of multiple pathways. Interestingly, biogenesis of miR-215 and several miRNAs is accelerated post-transcriptionally by hypoxia-inducible factors (HIFs) through HIF-Drosha interaction. Moreover, miR-215 expression correlates inversely with KDM1B while correlating positively with HIF1α and GBM progression in patients. These findings reveal a direct role of HIF in regulating miRNA biogenesis and consequently activating the miR-215-KDM1B-mediated signaling required for GIC adaptation to hypoxia.

Authors
Hu, J; Sun, T; Wang, H; Chen, Z; Wang, S; Yuan, L; Liu, T; Li, H-R; Wang, P; Feng, Y; Wang, Q; McLendon, RE; Friedman, AH; Keir, ST; Bigner, DD; Rathmell, J; Fu, X-D; Li, Q-J; Wang, H; Wang, X-F
MLA Citation
Hu, J, Sun, T, Wang, H, Chen, Z, Wang, S, Yuan, L, Liu, T, Li, H-R, Wang, P, Feng, Y, Wang, Q, McLendon, RE, Friedman, AH, Keir, ST, Bigner, DD, Rathmell, J, Fu, X-D, Li, Q-J, Wang, H, and Wang, X-F. "MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B." Cancer cell 29.1 (January 2016): 49-60.
Website
http://hdl.handle.net/10161/11667
PMID
26766590
Source
epmc
Published In
Cancer Cell
Volume
29
Issue
1
Publish Date
2016
Start Page
49
End Page
60
DOI
10.1016/j.ccell.2015.12.005

Abstract A157: Oncolytic poliovirus mediated immune events

Authors
Brown, MC; Holl, EK; Boczkowski, D; Bigner, DD; Gromeier, M; Nair, SK
MLA Citation
Brown, MC, Holl, EK, Boczkowski, D, Bigner, DD, Gromeier, M, and Nair, SK. "Abstract A157: Oncolytic poliovirus mediated immune events." Cancer Immunology Research 4.1 Supplement (January 2016): A157-A157.
Source
crossref
Published In
Cancer Immunology Research
Volume
4
Issue
1 Supplement
Publish Date
2016
Start Page
A157
End Page
A157
DOI
10.1158/2326-6074.CRICIMTEATIAACR15-A157

Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells.

Under normal physiologic conditions, the glutathione S-transferase P1 (GSTP1) protein exists intracellularly as a dimer in reversible equilibrium with its monomeric subunits. In the latter form, GSTP1 binds to the mitogen-activated protein kinase, JNK, and inhibits JNK downstream signaling. In tumor cells, which frequently are characterized by constitutively high GSTP1 expression, GSTP1 undergoes phosphorylation by epidermal growth factor receptor (EGFR) at tyrosine residues 3, 7, and 198. Here we report on the effect of this EGFR-dependent GSTP1 tyrosine phosphorylation on the interaction of GSTP1 with JNK, on the regulation of JNK downstream signaling by GSTP1, and on tumor cell survival. Using in vitro and in vivo growing human brain tumors, we show that tyrosine phosphorylation shifts the GSTP1 dimer-monomer equilibrium to the monomeric state and facilitates the formation of the GSTP1-JNK complex, in which JNK is functionally inhibited. Targeted mutagenesis and functional analysis demonstrated that the increased GSTP1 binding to JNK results from phosphorylation of the GSTP1 C-terminal Tyr-198 by EGFR and is associated with a >2.5-fold decrease in JNK downstream signaling and a significant suppression of both spontaneous and drug-induced apoptosis in the tumor cells. The findings define a novel mechanism of regulatory control of JNK signaling that is mediated by the EGFR/GSTP1 cross-talk and provides a survival advantage for tumors with activated EGFR and high GSTP1 expression. The results lay the foundation for a novel strategy of dual EGFR/GSTP1 for treating EGFR+ve, GSTP1 expressing GBMs.

Authors
Okamura, T; Antoun, G; Keir, ST; Friedman, H; Bigner, DD; Ali-Osman, F
MLA Citation
Okamura, T, Antoun, G, Keir, ST, Friedman, H, Bigner, DD, and Ali-Osman, F. "Phosphorylation of Glutathione S-Transferase P1 (GSTP1) by Epidermal Growth Factor Receptor (EGFR) Promotes Formation of the GSTP1-c-Jun N-terminal kinase (JNK) Complex and Suppresses JNK Downstream Signaling and Apoptosis in Brain Tumor Cells." The Journal of biological chemistry 290.52 (December 2015): 30866-30878.
PMID
26429914
Source
epmc
Published In
The Journal of biological chemistry
Volume
290
Issue
52
Publish Date
2015
Start Page
30866
End Page
30878
DOI
10.1074/jbc.m115.656140

Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma.

Generation of patient-derived, autologous dendritic cells (DCs) is a critical component of cancer immunotherapy with ex vivo-generated, tumor antigen-loaded DCs. An important factor in the ability to generate DCs is the potential impact of prior therapies on DC phenotype and function. We investigated the ability to generate DCs using cells harvested from pediatric patients with medulloblastoma for potential evaluation of DC-RNA based vaccination approach in this patient population. Cells harvested from medulloblastoma patient leukapheresis following induction chemotherapy and granulocyte colony stimulating factor mobilization were cryopreserved prior to use in DC generation. DCs were generated from the adherent CD14+ monocytes using standard procedures and analyzed for cell recovery, phenotype and function. To summarize, 4 out of 5 patients (80%) had sufficient monocyte recovery to permit DC generation, and we were able to generate DCs from 3 out of these 4 patient samples (75%). Overall, we successfully generated DCs that met phenotypic requisites for DC-based cancer therapy from 3 out of 5 (60%) patient samples and met both phenotypic and functional requisites from 2 out of 5 (40%) patient samples. This study highlights the potential to generate functional DCs for further clinical treatments from refractory patients that have been heavily pretreated with myelosuppressive chemotherapy. Here we demonstrate the utility of evaluating the effect of the currently employed standard-of-care therapies on the ex vivo generation of DCs for DC-based clinical studies in cancer patients.

Authors
Nair, SK; Driscoll, T; Boczkowski, D; Schmittling, R; Reynolds, R; Johnson, LA; Grant, G; Fuchs, H; Bigner, DD; Sampson, JH; Gururangan, S; Mitchell, DA
MLA Citation
Nair, SK, Driscoll, T, Boczkowski, D, Schmittling, R, Reynolds, R, Johnson, LA, Grant, G, Fuchs, H, Bigner, DD, Sampson, JH, Gururangan, S, and Mitchell, DA. "Ex vivo generation of dendritic cells from cryopreserved, post-induction chemotherapy, mobilized leukapheresis from pediatric patients with medulloblastoma." Journal of neuro-oncology 125.1 (October 2015): 65-74.
PMID
26311248
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
125
Issue
1
Publish Date
2015
Start Page
65
End Page
74
DOI
10.1007/s11060-015-1890-2

Abstract 2435A: Identification and treatment data of xenografts representing TCGA-defined glioblastoma subtypes

Authors
Keir, ST; Rasheed, BA; Hoadley, KA; Roskoski, MA; Gasinski, D; Kwatra, MM; Friedman, HS; Bigner, DD
MLA Citation
Keir, ST, Rasheed, BA, Hoadley, KA, Roskoski, MA, Gasinski, D, Kwatra, MM, Friedman, HS, and Bigner, DD. "Abstract 2435A: Identification and treatment data of xenografts representing TCGA-defined glioblastoma subtypes." August 1, 2015.
Source
crossref
Published In
Cancer Research
Volume
75
Issue
15 Supplement
Publish Date
2015
Start Page
2435A
End Page
2435A
DOI
10.1158/1538-7445.AM2015-2435A

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas.We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes.Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma.The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

Authors
Brat, DJ; Verhaak, RGW; Aldape, KD; Yung, WKA; Salama, SR; Cooper, LAD; Rheinbay, E; Miller, CR; Vitucci, M; Morozova, O; Robertson, AG; Noushmehr, H; Laird, PW; Cherniack, AD; Akbani, R; Huse, JT; Ciriello, G; Poisson, LM; Barnholtz-Sloan, JS; Berger, MS; Brennan, C; Colen, RR; Colman, H; Flanders, AE; Giannini, C; Grifford, M; Iavarone, A; Jain, R; Joseph, I; Kim, J; Kasaian, K; Mikkelsen, T; Murray, BA; O'Neill, BP; Pachter, L; Parsons, DW; Sougnez, C; Sulman, EP; Vandenberg, SR et al.
MLA Citation
Brat, DJ, Verhaak, RGW, Aldape, KD, Yung, WKA, Salama, SR, Cooper, LAD, Rheinbay, E, Miller, CR, Vitucci, M, Morozova, O, Robertson, AG, Noushmehr, H, Laird, PW, Cherniack, AD, Akbani, R, Huse, JT, Ciriello, G, Poisson, LM, Barnholtz-Sloan, JS, Berger, MS, Brennan, C, Colen, RR, Colman, H, Flanders, AE, Giannini, C, Grifford, M, Iavarone, A, Jain, R, Joseph, I, Kim, J, Kasaian, K, Mikkelsen, T, Murray, BA, O'Neill, BP, Pachter, L, Parsons, DW, Sougnez, C, Sulman, EP, and Vandenberg, SR et al. "Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas." The New England journal of medicine 372.26 (June 10, 2015): 2481-2498.
PMID
26061751
Source
epmc
Published In
The New England journal of medicine
Volume
372
Issue
26
Publish Date
2015
Start Page
2481
End Page
2498
DOI
10.1056/nejmoa1402121

A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study.

The epidermal growth factor receptor variant III deletion mutation, EGFRvIII, is expressed in ∼30% of primary glioblastoma and linked to poor long-term survival. Rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin. In previous phase II trials (ACTIVATE/ACT II), rindopepimut was well tolerated with robust EGFRvIII-specific immune responses and promising progression-free and overall survival. This multicenter, single-arm phase II clinical trial (ACT III) was performed to confirm these results.Rindopepimut and standard adjuvant temozolomide chemotherapy were administered to 65 patients with newly diagnosed EGFRvIII-expressing (EGFRvIII+) glioblastoma after gross total resection and chemoradiation.Progression-free survival at 5.5 months (∼8.5 mo from diagnosis) was 66%. Relative to study entry, median overall survival was 21.8 months, and 36-month overall survival was 26%. Extended rindopepimut vaccination (up to 3.5+ years) was well tolerated. Grades 1-2 injection site reactions were frequent. Anti-EGFRvIII antibody titers increased ≥4-fold in 85% of patients, and increased with duration of treatment. EGFRvIII was eliminated in 4/6 (67%) tumor samples obtained after >3 months of therapy.This study confirms, in a multicenter setting, the preliminary results seen in previous phase II trials of rindopepimut. A pivotal, double-blind, randomized, phase III trial ("ACT IV") is under way.

Authors
Schuster, J; Lai, RK; Recht, LD; Reardon, DA; Paleologos, NA; Groves, MD; Mrugala, MM; Jensen, R; Baehring, JM; Sloan, A; Archer, GE; Bigner, DD; Cruickshank, S; Green, JA; Keler, T; Davis, TA; Heimberger, AB; Sampson, JH
MLA Citation
Schuster, J, Lai, RK, Recht, LD, Reardon, DA, Paleologos, NA, Groves, MD, Mrugala, MM, Jensen, R, Baehring, JM, Sloan, A, Archer, GE, Bigner, DD, Cruickshank, S, Green, JA, Keler, T, Davis, TA, Heimberger, AB, and Sampson, JH. "A phase II, multicenter trial of rindopepimut (CDX-110) in newly diagnosed glioblastoma: the ACT III study." Neuro-oncology 17.6 (June 2015): 854-861.
PMID
25586468
Source
epmc
Published In
Neuro-Oncology
Volume
17
Issue
6
Publish Date
2015
Start Page
854
End Page
861
DOI
10.1093/neuonc/nou348

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.

The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR. The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. We validated proteomic profiles using patient-derived glioblastoma xenografts (PDGX), characterizing 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. Proteins found to be associated with high EGFR activity represent potential biomarkers for GBM monitoring.

Authors
Brown, KE; Chagoya, G; Kwatra, SG; Yen, T; Keir, ST; Cooter, M; Hoadley, KA; Rasheed, A; Lipp, ES; Mclendon, R; Ali-Osman, F; Bigner, DD; Sampson, JH; Kwatra, MM
MLA Citation
Brown, KE, Chagoya, G, Kwatra, SG, Yen, T, Keir, ST, Cooter, M, Hoadley, KA, Rasheed, A, Lipp, ES, Mclendon, R, Ali-Osman, F, Bigner, DD, Sampson, JH, and Kwatra, MM. "Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development." Journal of neurochemistry 133.5 (June 2015): 730-738.
PMID
25598002
Source
epmc
Published In
Journal of Neurochemistry
Volume
133
Issue
5
Publish Date
2015
Start Page
730
End Page
738
DOI
10.1111/jnc.13032

INHIBITION OF EPIGENETIC REGULATION AS A THERAPY FOR PEDIATRIC HIGH GRADE GLIOMA

Authors
Dombrowski, S; Abou-Antoun, T; Mack, S; Li, X-N; Houghton, P; Bigner, D; Rich, J; Recinos, V
MLA Citation
Dombrowski, S, Abou-Antoun, T, Mack, S, Li, X-N, Houghton, P, Bigner, D, Rich, J, and Recinos, V. "INHIBITION OF EPIGENETIC REGULATION AS A THERAPY FOR PEDIATRIC HIGH GRADE GLIOMA." June 2015.
Source
wos-lite
Published In
Neuro-Oncology
Volume
17
Publish Date
2015
Start Page
11
End Page
11

Phase I study of combination of antitumor immunotherapy targeted against cytomegalovirus (CMV) plus regulatory T-cell inhibition in patients with newly diagnosed glioblastoma multiforme (GBM).

Authors
Vlahovic, G; Archer, GE; Lally-Goss, D; Reap, E; Desjardins, A; Peters, KB; Randazzo, D; Healy, P; Herndon, JE; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Vlahovic, G, Archer, GE, Lally-Goss, D, Reap, E, Desjardins, A, Peters, KB, Randazzo, D, Healy, P, Herndon, JE, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Phase I study of combination of antitumor immunotherapy targeted against cytomegalovirus (CMV) plus regulatory T-cell inhibition in patients with newly diagnosed glioblastoma multiforme (GBM)." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma (GBM): Optimal dose determination.

Authors
Desjardins, A; Sampson, JH; Peters, KB; Vlahovic, G; Randazzo, D; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Lipp, ES; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, A, Sampson, JH, Peters, KB, Vlahovic, G, Randazzo, D, Threatt, S, Herndon, JE, Boulton, S, Lally-Goss, D, McSherry, F, Lipp, ES, Friedman, AH, Friedman, HS, Bigner, DD, and Gromeier, M. "Oncolytic polio/rhinovirus recombinant (PVSRIPO) against recurrent glioblastoma (GBM): Optimal dose determination." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients.

After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.

Authors
Mitchell, DA; Batich, KA; Gunn, MD; Huang, M-N; Sanchez-Perez, L; Nair, SK; Congdon, KL; Reap, EA; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; Coan, A; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Batich, KA, Gunn, MD, Huang, M-N, Sanchez-Perez, L, Nair, SK, Congdon, KL, Reap, EA, Archer, GE, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, Coan, A, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Sampson, JH. "Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients." Nature 519.7543 (March 11, 2015): 366-369.
PMID
25762141
Source
epmc
Published In
Nature
Volume
519
Issue
7543
Publish Date
2015
Start Page
366
End Page
369
DOI
10.1038/nature14320

Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas.

Adoptive cellular therapy (ACT) after lymphodepletive conditioning can induce dramatic clinical responses, but this approach has been largely limited to melanoma due to a lack of reliable methods for expanding tumor-specific lymphocytes from the majority of other solid cancers. We have employed tumor RNA-pulsed dendritic cells (DCs) to reliably expand CD4(+) and CD8(+) tumor-reactive T lymphocytes for curative ACT in a highly-invasive, chemotherapy- and radiation-resistant malignant glioma model. Curative treatment of established intracranial tumors involved a synergistic interaction between myeloablative (MA) conditioning, adoptively transferred tumor-specific T cells, and tumor RNA-pulsed DC vaccines. Hematopoietic stem cells (HSCs), administered for salvage from MA conditioning, rapidly migrated to areas of intracranial tumor growth and facilitated the recruitment of tumor-specific lymphocytes through HSC-elaborated chemokines and enhanced immunologic rejection of intracranial tumors during ACT. Furthermore, HSC transplant under non-myeloablative (NMA) conditions also enhanced immunologic tumor rejection, indicating a novel role for the use of HSCs in the immunologic treatment of malignant gliomas and possibly other solid tumors.

Authors
Flores, C; Pham, C; Snyder, D; Yang, S; Sanchez-Perez, L; Sayour, E; Cui, X; Kemeny, H; Friedman, H; Bigner, DD; Sampson, J; Mitchell, DA
MLA Citation
Flores, C, Pham, C, Snyder, D, Yang, S, Sanchez-Perez, L, Sayour, E, Cui, X, Kemeny, H, Friedman, H, Bigner, DD, Sampson, J, and Mitchell, DA. "Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas." Oncoimmunology 4.3 (March 2015): e994374-.
PMID
25949916
Source
epmc
Published In
OncoImmunology
Volume
4
Issue
3
Publish Date
2015
Start Page
e994374
DOI
10.4161/2162402x.2014.994374

Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas

Authors
Flores, C; Pham, C; Snyder, D; Yang, S; Sanchez-Perez, L; Sayour, E; Cui, X; Kemeny, H; Friedman, H; Bigner, DD; Sampson, J; Mitchell, DA
MLA Citation
Flores, C, Pham, C, Snyder, D, Yang, S, Sanchez-Perez, L, Sayour, E, Cui, X, Kemeny, H, Friedman, H, Bigner, DD, Sampson, J, and Mitchell, DA. "Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas." ONCOIMMUNOLOGY 4.3 (March 2015).
Source
wos-lite
Published In
OncoImmunology
Volume
4
Issue
3
Publish Date
2015
DOI
10.4161/2162402X.2014.9943741

Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: Implications for drug development

© 2015 International Society for Neurochemistry.The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR.

Authors
Brown, KE; Chagoya, G; Kwatra, SG; Yen, T; Keir, ST; Cooter, M; Hoadley, KA; Rasheed, A; Lipp, ES; McLendon, R; Ali-Osman, F; Bigner, DD; Sampson, JH; Kwatra, MM
MLA Citation
Brown, KE, Chagoya, G, Kwatra, SG, Yen, T, Keir, ST, Cooter, M, Hoadley, KA, Rasheed, A, Lipp, ES, McLendon, R, Ali-Osman, F, Bigner, DD, Sampson, JH, and Kwatra, MM. "Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: Implications for drug development." Journal of Neurochemistry 133.5 (2015): 730-738.
Source
scival
Published In
Journal of Neurochemistry
Volume
133
Issue
5
Publish Date
2015
Start Page
730
End Page
738
DOI
10.1111/jnc.13032

IT-10 * SYNERGISTIC CELLULAR INTERACTIONS IN ADOPTIVE IMMUNOTHERAPY LEADS TO IMMUNOLOGIC REJECTION OF MALIGNANT GLIOMA

Authors
Flores, C; Pham, C; Snyder, D; Yang, S; Sanchez-Perez, L; Sayour, E; Cui, X; Kemeny, H; Friedman, H; Bigner, D; Sampson, J; Mitchell, D
MLA Citation
Flores, C, Pham, C, Snyder, D, Yang, S, Sanchez-Perez, L, Sayour, E, Cui, X, Kemeny, H, Friedman, H, Bigner, D, Sampson, J, and Mitchell, D. "IT-10 * SYNERGISTIC CELLULAR INTERACTIONS IN ADOPTIVE IMMUNOTHERAPY LEADS TO IMMUNOLOGIC REJECTION OF MALIGNANT GLIOMA." Neuro-Oncology 16.suppl 5 (November 1, 2014): v111-v111.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v111
End Page
v111
DOI
10.1093/neuonc/nou258.8

AT-21 * FINAL RESULTS OF A PHASE 1 TRIAL OF AN ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) AGAINST RECURRENT GLIOBLASTOMA (GBM)

Authors
Desjardins, A; Sampson, J; Peters, K; Vlahovic, G; Threatt, S; Herndon, J; Boulton, S; Lally-Goss, D; McSherry, F; Lipp, E; Friedman, A; Friedman, H; Bigner, D; Gromeier, M
MLA Citation
Desjardins, A, Sampson, J, Peters, K, Vlahovic, G, Threatt, S, Herndon, J, Boulton, S, Lally-Goss, D, McSherry, F, Lipp, E, Friedman, A, Friedman, H, Bigner, D, and Gromeier, M. "AT-21 * FINAL RESULTS OF A PHASE 1 TRIAL OF AN ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) AGAINST RECURRENT GLIOBLASTOMA (GBM)." Neuro-Oncology 16.suppl 5 (November 1, 2014): v13-v13.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v13
End Page
v13
DOI
10.1093/neuonc/nou237.21

IT-34 * PILOT STUDY OF COMBINATION OF ANTITUMOR IMMUNOTHERAPY TARGETED AGAINST CYTOMEGALOVIRUS (CMV) PLUS REGULATORY T-CELL INHIBITION IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM)

Authors
Vlahovic, G; Archer, G; Lally-Goss, D; Reap, E; Batich, K; Desjardins, A; Peters, K; Ranjan, T; Healy, P; Herndon, J; Friedman, A; Friedman, H; Bigner, D; Sampson, J
MLA Citation
Vlahovic, G, Archer, G, Lally-Goss, D, Reap, E, Batich, K, Desjardins, A, Peters, K, Ranjan, T, Healy, P, Herndon, J, Friedman, A, Friedman, H, Bigner, D, and Sampson, J. "IT-34 * PILOT STUDY OF COMBINATION OF ANTITUMOR IMMUNOTHERAPY TARGETED AGAINST CYTOMEGALOVIRUS (CMV) PLUS REGULATORY T-CELL INHIBITION IN PATIENTS WITH NEWLY-DIAGNOSED GLIOBLASTOMA MULTIFORME (GBM)." Neuro-Oncology 16.suppl 5 (November 1, 2014): v117-v117.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v117
End Page
v117
DOI
10.1093/neuonc/nou258.32

ET-28 * COMBINATION THERAPY WITH MET TYROSINE KINASE INHIBITOR EMD1214063 AND BEVACIZUMAB

Authors
Keir, S; Roskoski, M; Gasinski, D; Friedman, H; Bigner, D
MLA Citation
Keir, S, Roskoski, M, Gasinski, D, Friedman, H, and Bigner, D. "ET-28 * COMBINATION THERAPY WITH MET TYROSINE KINASE INHIBITOR EMD1214063 AND BEVACIZUMAB." Neuro-Oncology 16.suppl 5 (November 1, 2014): v85-v85.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v85
End Page
v85
DOI
10.1093/neuonc/nou255.28

Oncolytic polio virotherapy of cancer.

Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct tumor cytotoxicity (oncolytic virotherapy), recently, the proinflammatory and immunogenic effects of viral tumor infection (oncolytic immunotherapy) have come into focus. Indeed, a capacity for eliciting broad, sustained antineoplastic effects stemming from combined direct viral cytotoxicity, innate antiviral activation, stromal proinflammatory stimulation, and recruitment of adaptive immune effector responses is the greatest asset of oncolytic viruses. However, it also is the source for enormous mechanistic complexity that must be considered for successful clinical translation. Because of fundamentally different relationships with their hosts (malignant or not), diverse replication strategies, and distinct modes of tumor cytotoxicity/killing, oncolytic viruses should not be referred to collectively. These agents must be evaluated based on their individual merits. In this review, the authors highlight key mechanistic principles of cancer treatment with the polio:rhinovirus chimera PVSRIPO and their implications for oncolytic immunotherapy in the clinic.

Authors
Brown, MC; Dobrikova, EY; Dobrikov, MI; Walton, RW; Gemberling, SL; Nair, SK; Desjardins, A; Sampson, JH; Friedman, HS; Friedman, AH; Tyler, DS; Bigner, DD; Gromeier, M
MLA Citation
Brown, MC, Dobrikova, EY, Dobrikov, MI, Walton, RW, Gemberling, SL, Nair, SK, Desjardins, A, Sampson, JH, Friedman, HS, Friedman, AH, Tyler, DS, Bigner, DD, and Gromeier, M. "Oncolytic polio virotherapy of cancer." Cancer 120.21 (November 2014): 3277-3286. (Review)
PMID
24939611
Source
epmc
Published In
Cancer
Volume
120
Issue
21
Publish Date
2014
Start Page
3277
End Page
3286
DOI
10.1002/cncr.28862

Induction of viral, 7-methyl-guanosine cap-independent translation and oncolysis by mitogen-activated protein kinase-interacting kinase-mediated effects on the serine/arginine-rich protein kinase.

Protein synthesis, the most energy-consuming process in cells, responds to changing physiologic priorities, e.g., upon mitogen- or stress-induced adaptations signaled through the mitogen-activated protein kinases (MAPKs). The prevailing status of protein synthesis machinery is a viral pathogenesis factor, particularly for plus-strand RNA viruses, where immediate translation of incoming viral RNAs shapes host-virus interactions. In this study, we unraveled signaling pathways centered on the ERK1/2 and p38α MAPK-interacting kinases MNK1/2 and their role in controlling 7-methyl-guanosine (m(7)G) "cap"-independent translation at enterovirus type 1 internal ribosomal entry sites (IRESs). Activation of Raf-MEK-ERK1/2 signals induced viral IRES-mediated translation in a manner dependent on MNK1/2. This effect was not due to MNK's known functions as eukaryotic initiation factor (eIF) 4G binding partner or eIF4E(S209) kinase. Rather, MNK catalytic activity enabled viral IRES-mediated translation/host cell cytotoxicity through negative regulation of the Ser/Arg (SR)-rich protein kinase (SRPK). Our investigations suggest that SRPK activity is a major determinant of type 1 IRES competency, host cell cytotoxicity, and viral proliferation in infected cells.We are targeting unfettered enterovirus IRES activity in cancer with PVSRIPO, the type 1 live-attenuated poliovirus (PV) (Sabin) vaccine containing a human rhinovirus type 2 (HRV2) IRES. A phase I clinical trial of PVSRIPO with intratumoral inoculation in patients with recurrent glioblastoma (GBM) is showing early promise. Viral translation proficiency in infected GBM cells is a core requirement for the antineoplastic efficacy of PVSRIPO. Therefore, it is critically important to understand the mechanisms controlling viral cap-independent translation in infected host cells.

Authors
Brown, MC; Bryant, JD; Dobrikova, EY; Shveygert, M; Bradrick, SS; Chandramohan, V; Bigner, DD; Gromeier, M
MLA Citation
Brown, MC, Bryant, JD, Dobrikova, EY, Shveygert, M, Bradrick, SS, Chandramohan, V, Bigner, DD, and Gromeier, M. "Induction of viral, 7-methyl-guanosine cap-independent translation and oncolysis by mitogen-activated protein kinase-interacting kinase-mediated effects on the serine/arginine-rich protein kinase." Journal of virology 88.22 (November 2014): 13135-13148.
PMID
25187541
Source
epmc
Published In
Journal of virology
Volume
88
Issue
22
Publish Date
2014
Start Page
13135
End Page
13148
DOI
10.1128/jvi.01883-14

Abstract LB-82: MLL2 maintains neoplastic cell growth and global histone H3 lysine 4 monomethylation

Authors
Guo, C; Chen, LH; Huang, Y; Chang, C-C; Wang, P; Pirozzi, CJ; Qin, X; Bao, X; Greer, PK; McLendon, RE; Yan, H; Keir, ST; Bigner, DD; He, Y
MLA Citation
Guo, C, Chen, LH, Huang, Y, Chang, C-C, Wang, P, Pirozzi, CJ, Qin, X, Bao, X, Greer, PK, McLendon, RE, Yan, H, Keir, ST, Bigner, DD, and He, Y. "Abstract LB-82: MLL2 maintains neoplastic cell growth and global histone H3 lysine 4 monomethylation." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
LB-82
End Page
LB-82
DOI
10.1158/1538-7445.AM2014-LB-82

Abstract 63: Driving brain tumorigenesis: Generation of a mutant IDH1 mouse model of progressive glioma

Authors
Pirozzi, CJ; Wang, CY; Carpenter, AB; Zhu, H; Greer, PK; McLendon, RE; Bigner, DD; He, Y; Yan, H
MLA Citation
Pirozzi, CJ, Wang, CY, Carpenter, AB, Zhu, H, Greer, PK, McLendon, RE, Bigner, DD, He, Y, and Yan, H. "Abstract 63: Driving brain tumorigenesis: Generation of a mutant IDH1 mouse model of progressive glioma." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
63
End Page
63
DOI
10.1158/1538-7445.AM2014-63

Abstract CT416: Intratumoral administration of an Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) in recurrent glioblastoma (GBM): Preliminary results of the Phase I clinical trial

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Friedman, A; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, A, Sampson, JH, Peters, KB, Ranjan, T, Vlahovic, G, Threatt, S, Herndon, JE, Boulton, S, Lally-Goss, D, McSherry, F, Friedman, A, Friedman, HS, Bigner, DD, and Gromeier, M. "Abstract CT416: Intratumoral administration of an Oncolytic Polio/Rhinovirus Recombinant (PVSRIPO) in recurrent glioblastoma (GBM): Preliminary results of the Phase I clinical trial." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
CT416
End Page
CT416
DOI
10.1158/1538-7445.AM2014-CT416

Abstract 838: Establishment, identification and treatment data of TCGA glioblatoma xenograft subtypes

Authors
Keir, ST; Rasheed, BA; Hoadley, KA; Roskoski, MA; Gasinski, D; Killela, PJ; Yan, H; Kwatra, MM; Friedman, HS; Bigner, DD
MLA Citation
Keir, ST, Rasheed, BA, Hoadley, KA, Roskoski, MA, Gasinski, D, Killela, PJ, Yan, H, Kwatra, MM, Friedman, HS, and Bigner, DD. "Abstract 838: Establishment, identification and treatment data of TCGA glioblatoma xenograft subtypes." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
838
End Page
838
DOI
10.1158/1538-7445.AM2014-838

AJAP1 is dysregulated at an early stage of gliomagenesis and suppresses invasion through cytoskeleton reorganization

Authors
Han, L; Zhang, K-L; Zhang, J-X; Zeng, L; Di, C-H; Fee, B; Rivas, M; Jiang, T; Bigner, D; Kang, C-S; Adamson, DC
MLA Citation
Han, L, Zhang, K-L, Zhang, J-X, Zeng, L, Di, C-H, Fee, B, Rivas, M, Jiang, T, Bigner, D, Kang, C-S, and Adamson, DC. "AJAP1 is dysregulated at an early stage of gliomagenesis and suppresses invasion through cytoskeleton reorganization." October 1, 2014.
Source
wos-lite
Published In
Cancer Research
Volume
74
Issue
19
Publish Date
2014
DOI
10.1158/1538-7445.AM2014-1561

miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways.

Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Glioma-initiating cells (GICs) are stem-like cells that have been implicated in glioblastoma progression and recurrence; however, the distinct properties of GICs and non-GICs within GBM tumors are largely uncharacterized. Here, we evaluated stem cell-associated microRNA (miR) expression in GICs from GBM patients and GICs derived from xenografted human glioma cell lines and determined that miR-33a promotes GIC growth and self-renewal. Moreover, evaluation of a GBM tissue array revealed that higher miR-33a expression was associated with poor prognosis of GBM patients. Antagonizing miR-33a function in GICs reduced self-renewal and tumor progression in immune-compromised mice, whereas overexpression of miR-33a in non-GICs promoted the display of features associated with GICs. We identified the mRNAs encoding phosphodiesterase 8A (PDE8A) and UV radiation resistance-associated gene (UVRAG) as direct miR-33a targets. PDE8A and UVRAG negatively regulated the cAMP/PKA and NOTCH pathways, respectively; therefore, miR-33a-dependent reduction of these proteins promoted growth and self-renewal of GICs by enhancing PKA and NOTCH activity. Furthermore, in GBM specimens, there was an inverse correlation between the expression levels of miR-33a and PDE8A and UVRAG expression. These findings reveal a miR-33a-centered signaling network that promotes GIC maintenance and has potential as a therapeutic target for GBM treatment.

Authors
Wang, H; Sun, T; Hu, J; Zhang, R; Rao, Y; Wang, S; Chen, R; McLendon, RE; Friedman, AH; Keir, ST; Bigner, DD; Li, Q-J; Wang, H; Wang, X-F
MLA Citation
Wang, H, Sun, T, Hu, J, Zhang, R, Rao, Y, Wang, S, Chen, R, McLendon, RE, Friedman, AH, Keir, ST, Bigner, DD, Li, Q-J, Wang, H, and Wang, X-F. "miR-33a promotes glioma-initiating cell self-renewal via PKA and NOTCH pathways." The Journal of clinical investigation 124.10 (October 2014): 4489-4502.
PMID
25202981
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
10
Publish Date
2014
Start Page
4489
End Page
4502
DOI
10.1172/jci75284

EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis.

Aberrant activation of EGFR in human cancers promotes tumorigenesis through stimulation of AKT signaling. Here, we determined that the discoidina neuropilin-like membrane protein DCBLD2 is upregulated in clinical specimens of glioblastomas and head and neck cancers (HNCs) and is required for EGFR-stimulated tumorigenesis. In multiple cancer cell lines, EGFR activated phosphorylation of tyrosine 750 (Y750) of DCBLD2, which is located within a recently identified binding motif for TNF receptor-associated factor 6 (TRAF6). Consequently, phosphorylation of DCBLD2 Y750 recruited TRAF6, leading to increased TRAF6 E3 ubiquitin ligase activity and subsequent activation of AKT, thereby enhancing EGFR-driven tumorigenesis. Moreover, evaluation of patient samples of gliomas and HNCs revealed an association among EGFR activation, DCBLD2 phosphorylation, and poor prognoses. Together, our findings uncover a pathway in which DCBLD2 functions as a signal relay for oncogenic EGFR signaling to promote tumorigenesis and suggest DCBLD2 and TRAF6 as potential therapeutic targets for human cancers that are associated with EGFR activation.

Authors
Feng, H; Lopez, GY; Kim, CK; Alvarez, A; Duncan, CG; Nishikawa, R; Nagane, M; Su, A-JA; Auron, PE; Hedberg, ML; Wang, L; Raizer, JJ; Kessler, JA; Parsa, AT; Gao, W-Q; Kim, S-H; Minata, M; Nakano, I; Grandis, JR; McLendon, RE; Bigner, DD; Lin, H-K; Furnari, FB; Cavenee, WK; Hu, B; Yan, H; Cheng, S-Y
MLA Citation
Feng, H, Lopez, GY, Kim, CK, Alvarez, A, Duncan, CG, Nishikawa, R, Nagane, M, Su, A-JA, Auron, PE, Hedberg, ML, Wang, L, Raizer, JJ, Kessler, JA, Parsa, AT, Gao, W-Q, Kim, S-H, Minata, M, Nakano, I, Grandis, JR, McLendon, RE, Bigner, DD, Lin, H-K, Furnari, FB, Cavenee, WK, Hu, B, Yan, H, and Cheng, S-Y. "EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis." The Journal of clinical investigation 124.9 (September 2014): 3741-3756.
PMID
25061874
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
9
Publish Date
2014
Start Page
3741
End Page
3756
DOI
10.1172/jci73093

EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis

Authors
Feng, H; Lopez, GY; Kim, CK; Alvarez, A; Duncan, CG; Nishikawa, R; Nagane, M; Su, A-JA; Auron, PE; Hedberg, ML; Wang, L; Raizer, JJ; Kessler, JA; Parsa, AT; Gao, W-Q; Kim, S-H; Minata, M; Nakano, I; Grandis, JR; McLendon, RE; Bigner, DD; Lin, H-K; Furnari, FB; Cavenee, WK; Hu, B; Yan, H; Cheng, S-Y
MLA Citation
Feng, H, Lopez, GY, Kim, CK, Alvarez, A, Duncan, CG, Nishikawa, R, Nagane, M, Su, A-JA, Auron, PE, Hedberg, ML, Wang, L, Raizer, JJ, Kessler, JA, Parsa, AT, Gao, W-Q, Kim, S-H, Minata, M, Nakano, I, Grandis, JR, McLendon, RE, Bigner, DD, Lin, H-K, Furnari, FB, Cavenee, WK, Hu, B, Yan, H, and Cheng, S-Y. "EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis." JOURNAL OF CLINICAL INVESTIGATION 124.9 (September 2014): 3741-3756.
Source
wos-lite
Published In
Journal of Clinical Investigation
Volume
124
Issue
9
Publish Date
2014
Start Page
3741
End Page
3756
DOI
10.1172/JC173093

Malignant brainstem gliomas in adults: clinicopathological characteristics and prognostic factors.

Adult malignant brainstem gliomas (BSGs) are poorly characterized due to their relative rarity. We have examined histopathologically confirmed cases of adult malignant BSGs to better characterize the patient and tumor features and outcomes, including the natural history, presentation, imaging, molecular characteristics, prognostic factors, and appropriate treatments. A total of 34 patients were identified, consisting of 22 anaplastic astrocytomas (AAs) and 12 glioblastomas (GBMs). The overall median survival for all patients was 25.8 months, with patients having GBMs experiencing significantly worse survival (12.1 vs. 77.0 months, p = 0.0011). The majority of tumors revealed immunoreactivity for EGFR (93.3 %) and MGMT (64.7 %). Most tumors also exhibited chromosomal abnormalities affecting the loci of epidermal growth factor receptor (92.9 %), MET (100 %), PTEN (61.5 %), and 9p21 (80 %). AAs more commonly appeared diffusely enhancing (50.0 vs. 27.3 %) or diffusely nonenhancing (25.0 vs. 0.0 %), while GBMs were more likely to exhibit focal enhancement (54.6 vs. 10.0 %). Multivariate analysis revealed confirmed histopathology for GBM to significantly affect survival (HR 4.80; 95 % CI 1.86-12.4; p = 0.0012). In conclusion, adult malignant BSGs have an overall poor prognosis, with GBM tumors faring significantly worse than AAs. As AAs and GBMs have differing imaging characteristics, tissue diagnosis may be necessary to accurately determine patient prognosis and identify molecular characteristics which may aid in the treatment of these aggressive tumors.

Authors
Babu, R; Kranz, PG; Agarwal, V; McLendon, RE; Thomas, S; Friedman, AH; Bigner, DD; Adamson, C
MLA Citation
Babu, R, Kranz, PG, Agarwal, V, McLendon, RE, Thomas, S, Friedman, AH, Bigner, DD, and Adamson, C. "Malignant brainstem gliomas in adults: clinicopathological characteristics and prognostic factors." Journal of neuro-oncology 119.1 (August 2014): 177-185.
PMID
24838419
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
119
Issue
1
Publish Date
2014
Start Page
177
End Page
185
DOI
10.1007/s11060-014-1471-9

NEXT-GENERATION RECOMBINANT IMMUNOTOXINS FOR GLIOBLASTOMAS AND MELANOMAS TREATMENT

Authors
Kuan, C-T; Pastan, IH; Bigner, DD
MLA Citation
Kuan, C-T, Pastan, IH, and Bigner, DD. "NEXT-GENERATION RECOMBINANT IMMUNOTOXINS FOR GLIOBLASTOMAS AND MELANOMAS TREATMENT." July 1, 2014.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 3
Publish Date
2014
Start Page
iii43
End Page
iii43
DOI
10.1093/neuonc/nou209.6

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas.

Gliomas arising in the brainstem and thalamus are devastating tumors that are difficult to surgically resect. To determine the genetic and epigenetic landscape of these tumors, we performed exomic sequencing of 14 brainstem gliomas (BSGs) and 12 thalamic gliomas. We also performed targeted mutational analysis of an additional 24 such tumors and genome-wide methylation profiling of 45 gliomas. This study led to the discovery of tumor-specific mutations in PPM1D, encoding wild-type p53-induced protein phosphatase 1D (WIP1), in 37.5% of the BSGs that harbored hallmark H3F3A mutations encoding p.Lys27Met substitutions. PPM1D mutations were mutually exclusive with TP53 mutations in BSG and attenuated p53 activation in vitro. PPM1D mutations were truncating alterations in exon 6 that enhanced the ability of PPM1D to suppress the activation of the DNA damage response checkpoint protein CHK2. These results define PPM1D as a frequent target of somatic mutation and as a potential therapeutic target in brainstem gliomas.

Authors
Zhang, L; Chen, LH; Wan, H; Yang, R; Wang, Z; Feng, J; Yang, S; Jones, S; Wang, S; Zhou, W; Zhu, H; Killela, PJ; Zhang, J; Wu, Z; Li, G; Hao, S; Wang, Y; Webb, JB; Friedman, HS; Friedman, AH; McLendon, RE; He, Y; Reitman, ZJ; Bigner, DD; Yan, H
MLA Citation
Zhang, L, Chen, LH, Wan, H, Yang, R, Wang, Z, Feng, J, Yang, S, Jones, S, Wang, S, Zhou, W, Zhu, H, Killela, PJ, Zhang, J, Wu, Z, Li, G, Hao, S, Wang, Y, Webb, JB, Friedman, HS, Friedman, AH, McLendon, RE, He, Y, Reitman, ZJ, Bigner, DD, and Yan, H. "Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas." Nature genetics 46.7 (July 2014): 726-730.
PMID
24880341
Source
epmc
Published In
Nature Genetics
Volume
46
Issue
7
Publish Date
2014
Start Page
726
End Page
730
DOI
10.1038/ng.2995

Idh1 mutations as a immunotherapeutic target for brain tumors.

Immunotherapy promises an exquisitely precise therapeutic approach, and substantial evidence suggests that activated T cells can eradicate large tumors, even within the "immunologically privileged" brain. EGFRvIII and isocitrate dehydrogenase 1 (IDH1) mutations are two of the only consistent tumor-specific mutations that have been described. IDH1 is an evolutionarily-conserved enzyme essential to cell function. Greater than 90% of all IDH1 mutations occur from a substitution of histidine for arginine at codon 132, resulting in the highly conserved and tumor-specific mutation, IDH1R132H. IDH1R132H is homogeneously expressed in all tumor cells in tumors that express this mutation, including single infiltrating tumor cells but is absent in normal cells. The high frequency, specificity, and homogeneous expression of the IDH1 mutation make it an ideal target for therapeutic intervention.

Authors
Archer, GE; Reap, E; Norberg, P; Cui, X; Schmittling, R; Herndon, J; Chandramohan, V; Riccione, K; Kuan, CT; Yan, H; Bigner, DD; Sampson, JH
MLA Citation
Archer, GE, Reap, E, Norberg, P, Cui, X, Schmittling, R, Herndon, J, Chandramohan, V, Riccione, K, Kuan, CT, Yan, H, Bigner, DD, and Sampson, JH. "Idh1 mutations as a immunotherapeutic target for brain tumors." Neuro Oncol 16 Suppl 3 (July 2014): iii40-.
PMID
25165322
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii40
DOI
10.1093/neuonc/nou208.65

Oncolytic polio/rhinovirus recombinant (pvsripo) in recurrent glioblastoma (gbm): first phase I clinical trial evaluating the intratumoral administration.

PVSRIPO is the live attenuated, oral (SABIN) serotype 1 poliovirus vaccine containing a heterologous internal ribosomal entry site stemming from human rhinovirus type 2. PVSRIPO recognizes nectin-like molecule-5, an oncofetal cell adhesion molecule and tumor antigen widely expressed ectopically in malignancy. Within, we report on the ongoing phase I study evaluating the intratumoral convection-enhanced delivery (CED) of PVSRIPO.

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, A, Sampson, JH, Peters, KB, Ranjan, T, Vlahovic, G, Threatt, S, Herndon, JE, Boulton, S, Lally-Goss, D, McSherry, F, Friedman, AH, Friedman, HS, Bigner, DD, and Gromeier, M. "Oncolytic polio/rhinovirus recombinant (pvsripo) in recurrent glioblastoma (gbm): first phase I clinical trial evaluating the intratumoral administration." Neuro Oncol 16 Suppl 3 (July 2014): iii43-.
PMID
25165331
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii43
DOI
10.1093/neuonc/nou209.5

Oncolytic poliovirus immunotherapy of glioblastoma.

With the exception of Burkitt lymphoma, almost all solid cancers are susceptible to infection with poliovirus, due to widespread ectopic expression of the poliovirus receptor, the onco-fetal cell adhesion molecule Necl5/CD155. We engineered a profoundly CNS-incompetent and genetically stable variant of polio through recombination of the cognate internal ribosomal entry site (IRES) with its counterpart from human rhinovirus type 2. The resulting PVSRIPO chimera is incapable of causing poliomyelitis or encephalitis in non-human primates or human subjects, even after high-dose intracerebral inoculation, but retains excellent cytotoxic properties in malignant cells. This is due to constitutively active signal transduction pathways via Raf-Erk MAPKs to the MAPK-interacting kinase, Mnk, and the translation apparatus.

Authors
Gromeier, M; Dobrikova, E; Dobrikov, M; Brown, M; Bryant, J; Threatt, S; Boulton, S; Carter, K; Herndon, J; Desjardins, A; Friedman, H; Sampson, J; Friedman, A; Bigner, D
MLA Citation
Gromeier, M, Dobrikova, E, Dobrikov, M, Brown, M, Bryant, J, Threatt, S, Boulton, S, Carter, K, Herndon, J, Desjardins, A, Friedman, H, Sampson, J, Friedman, A, and Bigner, D. "Oncolytic poliovirus immunotherapy of glioblastoma." Neuro Oncol 16 Suppl 3 (July 2014): iii41-.
PMID
25165326
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii41
DOI
10.1093/neuonc/nou208.69

Tert promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.

Malignant cells must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas.

Authors
Yan, H; Killela, PJ; Reitman, ZJ; Jiao, Y; Bettegowda, C; Agrawal, N; Diaz, LA; Friedman, AH; Friedman, H; Gallia, GL; Giovanella, BC; Grollman, AP; He, TC; He, Y; Hruban, RH; Jallo, GI; Mandahl, N; Meeker, AK; Mertens, F; Netto, GJ; Rasheed, BA; Riggins, GJ; Rosenquist, TA; Schiffman, M; Shih, I; Theodorescu, D; Torbenson, MS; Velculescu, VE; Wang, TL; Wentzensen, N; Wood, LD; Zhang, M; Healy, P; Yang, R; Diplas, B; Wang, ZH; Greer, P; Zhu, HS; Wang, C; Carpenter, A; Herndon, JE; McLendon, RE et al.
MLA Citation
Yan, H, Killela, PJ, Reitman, ZJ, Jiao, Y, Bettegowda, C, Agrawal, N, Diaz, LA, Friedman, AH, Friedman, H, Gallia, GL, Giovanella, BC, Grollman, AP, He, TC, He, Y, Hruban, RH, Jallo, GI, Mandahl, N, Meeker, AK, Mertens, F, Netto, GJ, Rasheed, BA, Riggins, GJ, Rosenquist, TA, Schiffman, M, Shih, I, Theodorescu, D, Torbenson, MS, Velculescu, VE, Wang, TL, Wentzensen, N, Wood, LD, Zhang, M, Healy, P, Yang, R, Diplas, B, Wang, ZH, Greer, P, Zhu, HS, Wang, C, Carpenter, A, Herndon, JE, and McLendon, RE et al. "Tert promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal." Neuro Oncol 16 Suppl 3 (July 2014): iii5-iii6.
PMID
25165359
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii5
End Page
iii6
DOI
10.1093/neuonc/nou206.18

Identification and preliminary treatment data of xenografts representing tcga-defined subtypes.

The Cancer Genome Atlas (TCGA) Network recently catalogued recurrent genomic abnormalities in glioblastoma (GBM). This genomic profiling lead to the molecular classification of GBMs into four subtypes: Proneural, Neural, Classical and Mesenchymal. The importance of identifying these subtypes stands to help researchers and clinicians to better understand GBMs with the potential to personalize treatment options and explore different therapeutic approaches that each subtype may require. As such, the development of preclinical xenograft models that represent each TCGA subtype serves to expedite the evaluation of targeted therapeutic strategies for the treatment of GBMs.

Authors
Keir, ST; Roskoski, MA; Gasinski, D; Kwatra, MK; Friedman, HS; Bigner, DD
MLA Citation
Keir, ST, Roskoski, MA, Gasinski, D, Kwatra, MK, Friedman, HS, and Bigner, DD. "Identification and preliminary treatment data of xenografts representing tcga-defined subtypes." Neuro Oncol 16 Suppl 3 (July 2014): iii35-.
PMID
25165298
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii35
DOI
10.1093/neuonc/nou208.45

Patient-derived xenografts mirror the proteomic profile of human glioblastoma: implications for personalized drug development.

(blind field).

Authors
Kwatra, MM; Brown, KE; Chagoya, G; Keir, ST; Bigner, DD; Sampson, JH
MLA Citation
Kwatra, MM, Brown, KE, Chagoya, G, Keir, ST, Bigner, DD, and Sampson, JH. "Patient-derived xenografts mirror the proteomic profile of human glioblastoma: implications for personalized drug development." Neuro Oncol 16 Suppl 3 (July 2014): iii38-.
PMID
25165310
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii38
DOI
10.1093/neuonc/nou208.57

Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas

Authors
Zhang, L; Chen, LH; Wan, H; Yang, R; Wang, Z; Feng, J; Yang, S; Jones, S; Wang, S; Zhou, W; Zhu, H; Killela, PJ; Zhang, J; Wu, Z; Li, G; Hao, S; Wang, Y; Webb, JB; Friedman, HS; Friedman, AH; McLendon, RE; He, Y; Reitman, ZJ; Bigner, DD; Yan, H
MLA Citation
Zhang, L, Chen, LH, Wan, H, Yang, R, Wang, Z, Feng, J, Yang, S, Jones, S, Wang, S, Zhou, W, Zhu, H, Killela, PJ, Zhang, J, Wu, Z, Li, G, Hao, S, Wang, Y, Webb, JB, Friedman, HS, Friedman, AH, McLendon, RE, He, Y, Reitman, ZJ, Bigner, DD, and Yan, H. "Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas." Nature Genetics 46.7 (June 1, 2014): 726-730.
Source
crossref
Published In
Nature Genetics
Volume
46
Issue
7
Publish Date
2014
Start Page
726
End Page
730
DOI
10.1038/ng.2995

PRE-CLINICAL EFFICACY STUDY OF INTRA-THECAL (IT) (LU)-L-177-DOTA-TATE (SOMATOSTATIN ANALOGUE) IN ATHYMIC RATS WITH LEPTOMENINGEAL DISEASE (LMD) FROM MEDULLOBLASTOMA (MBL)

Authors
Vaidyanathan, G; Gururangan, S; Bigner, D; Zalutsky, M
MLA Citation
Vaidyanathan, G, Gururangan, S, Bigner, D, and Zalutsky, M. "PRE-CLINICAL EFFICACY STUDY OF INTRA-THECAL (IT) (LU)-L-177-DOTA-TATE (SOMATOSTATIN ANALOGUE) IN ATHYMIC RATS WITH LEPTOMENINGEAL DISEASE (LMD) FROM MEDULLOBLASTOMA (MBL)." June 2014.
Source
wos-lite
Published In
Neuro-Oncology
Volume
16
Publish Date
2014
Start Page
71
End Page
71

Phase I study of the intratumoral administration of an oncolytic polio/rhinovirus recombinant (PVSRIPO) in recurrent glioblastoma (GBM)

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Watts, J; Threatt, S; Herndon, JE; Boulton, S; Lally-Goss, D; McSherry, F; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, A, Sampson, JH, Peters, KB, Ranjan, T, Vlahovic, G, Watts, J, Threatt, S, Herndon, JE, Boulton, S, Lally-Goss, D, McSherry, F, Friedman, AH, Friedman, HS, Bigner, DD, and Gromeier, M. "Phase I study of the intratumoral administration of an oncolytic polio/rhinovirus recombinant (PVSRIPO) in recurrent glioblastoma (GBM)." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Regulatory T-cell inhibition plus antitumor immunotherapy targeted against cytomegalovirus (CMV) in patients with newly diagnosed glioblastoma multiforme (GBM).

Authors
Vlahovic, G; Archer, GE; Lally-Goss, D; Norman, S; Desjardins, A; Peters, KB; Ranjan, T; Watts, J; Healy, P; Herndon, JE; Friedman, HS; Friedman, AH; Bigner, DD; Sampson, JH
MLA Citation
Vlahovic, G, Archer, GE, Lally-Goss, D, Norman, S, Desjardins, A, Peters, KB, Ranjan, T, Watts, J, Healy, P, Herndon, JE, Friedman, HS, Friedman, AH, Bigner, DD, and Sampson, JH. "Regulatory T-cell inhibition plus antitumor immunotherapy targeted against cytomegalovirus (CMV) in patients with newly diagnosed glioblastoma multiforme (GBM)." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

AJAP1 is dysregulated at an early stage of gliomagenesis and suppresses invasion through cytoskeleton reorganization.

Down-regulation of AJAP1 in glioblastoma multiforme (GBM) has been reported. However, the expression profiles of AJAP1 in gliomas and the underlying mechanisms of AJAP1 function on invasion are still poorly understood.The gene profiles of AJAP1 in glioma patients were studied among four independent cohorts. Confocal imaging was used to analyze the AJAP1 localization. After AJAP1 overexpression in GBM cell lines, cellular polarity, cytoskeleton distribution, and antitumor effect were investigated in vitro and in vivo.AJAP1 expression was significantly decreased in gliomas compared with normal brain in REMBRANDT and CGCA cohorts. Additionally, low AJAP1 expression was associated with worse survival in GBMs in REMBRANDT and TCGA U133A cohorts and was significantly associated with classical and mesenchymal subtypes of GBMs among four cohorts. Confocal imaging indicated AJAP1 localized in cell membranes in low-grade gliomas and AJAP1-overexpressing GBM cells, but difficult to assess in high-grade gliomas due to its absence. AJAP1 overexpression altered the cytoskeleton and cellular polarity in vitro and inhibited the tumor growth in vivo.AJAP1 is dysregulated at an early stage of gliomagenesis and may suppress glioma cell invasion and proliferation, which suggests that AJAP1 may be a potential diagnostic and prognostic marker for gliomas.

Authors
Han, L; Zhang, K-L; Zhang, J-X; Zeng, L; Di, C-H; Fee, BE; Rivas, M; Bao, Z-S; Jiang, T; Bigner, D; Kang, C-S; Adamson, DC
MLA Citation
Han, L, Zhang, K-L, Zhang, J-X, Zeng, L, Di, C-H, Fee, BE, Rivas, M, Bao, Z-S, Jiang, T, Bigner, D, Kang, C-S, and Adamson, DC. "AJAP1 is dysregulated at an early stage of gliomagenesis and suppresses invasion through cytoskeleton reorganization." CNS neuroscience & therapeutics 20.5 (May 2014): 429-437.
PMID
24483339
Source
epmc
Published In
CNS Neuroscience and Therapeutics
Volume
20
Issue
5
Publish Date
2014
Start Page
429
End Page
437
DOI
10.1111/cns.12232

The Somatic Genomic Landscape of Glioblastoma

Authors
Brennan, CW; Verhaak, RGW; McKenna, A; Campos, B; Noushmehr, H; Salama, SR; Zheng, S; Chakravarty, D; Sanborn, JZ; Berman, SH; Beroukhim, R; Bernard, B; Wu, C-J; Genovese, G; Shmulevich, I; Barnholtz-Sloan, J; Zou, L; Vegesna, R; Shukla, SA; Ciriello, G; Yung, WK; Zhang, W; Sougnez, C; Mikkelsen, T; Aldape, K; Bigner, DD; Van Meir, EG; Prados, M; Sloan, A; Black, KL; Eschbacher, J; Finocchiaro, G; Friedman, W; Andrews, DW; Guha, A; Iacocca, M; O’Neill, BP; Foltz, G; Myers, J; Weisenberger, DJ et al.
MLA Citation
Brennan, CW, Verhaak, RGW, McKenna, A, Campos, B, Noushmehr, H, Salama, SR, Zheng, S, Chakravarty, D, Sanborn, JZ, Berman, SH, Beroukhim, R, Bernard, B, Wu, C-J, Genovese, G, Shmulevich, I, Barnholtz-Sloan, J, Zou, L, Vegesna, R, Shukla, SA, Ciriello, G, Yung, WK, Zhang, W, Sougnez, C, Mikkelsen, T, Aldape, K, Bigner, DD, Van Meir, EG, Prados, M, Sloan, A, Black, KL, Eschbacher, J, Finocchiaro, G, Friedman, W, Andrews, DW, Guha, A, Iacocca, M, O’Neill, BP, Foltz, G, Myers, J, and Weisenberger, DJ et al. "The Somatic Genomic Landscape of Glioblastoma." Cell 157.3 (April 2014): 753-753.
Source
crossref
Published In
Cell
Volume
157
Issue
3
Publish Date
2014
Start Page
753
End Page
753
DOI
10.1016/j.cell.2014.04.004

The genetic landscape of anaplastic astrocytoma.

Anaplastic astrocytoma WHO grade III (A3) is a lethal brain tumor that often occurs in middle aged patients. Clinically, it is challenging to distinguish A3 from glioblastoma multiforme (GBM) WHO grade IV. To reveal the genetic landscape of this tumor type, we sequenced the exome of a cohort of A3s (n=16). For comparison and to illuminate the genomic landscape of other glioma subtypes, we also included in our study diffuse astrocytoma WHO grade II (A2, n=7), oligoastrocytoma WHO grade II (OA2, n=2), anaplastic oligoastrocytoma WHO grade III (OA3, n=4), and GBM (n=28). Exome sequencing of A3s identified frequent mutations in IDH1 (75%, 12/16), ATRX (63%, 10/16), and TP53 (82%, 13/16). In contrast, the majority of GBMs (75%, 21/28) did not contain IDH1 or ATRX mutations, and displayed a distinct spectrum of mutations. Finally, our study also identified novel genes that were not previously linked to this tumor type. In particular, we found mutations in Notch pathway genes (NOTCH1, NOTCH2, NOTCH4, NOTCH2NL), including a recurrent NOTCH1-A465Tmutation, in 31% (5/16) of A3s. This study suggests genetic signatures will be useful for the classification of gliomas.

Authors
Killela, PJ; Pirozzi, CJ; Reitman, ZJ; Jones, S; Rasheed, BA; Lipp, E; Friedman, H; Friedman, AH; He, Y; McLendon, RE; Bigner, DD; Yan, H
MLA Citation
Killela, PJ, Pirozzi, CJ, Reitman, ZJ, Jones, S, Rasheed, BA, Lipp, E, Friedman, H, Friedman, AH, He, Y, McLendon, RE, Bigner, DD, and Yan, H. "The genetic landscape of anaplastic astrocytoma." Oncotarget 5.6 (March 30, 2014): 1452-1457.
PMID
24140581
Source
pubmed
Published In
Oncotarget
Volume
5
Issue
6
Publish Date
2014
Start Page
1452
End Page
1457
DOI
10.18632/oncotarget.1505

Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas.

Frequent mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and the promoter of telomerase reverse transcriptase (TERT) represent two significant discoveries in glioma genomics. Understanding the degree to which these two mutations co-occur or occur exclusively of one another in glioma subtypes presents a unique opportunity to guide glioma classification and prognosis. We analyzed the relationship between overall survival (OS) and the presence of IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas. We hypothesized and show that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of cases. Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS (11.5 months). Patients whose Grade III-IV gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months. Analyzing gliomas based on their genetic signatures allows for the stratification of these patients into distinct cohorts, with unique prognosis and survival.

Authors
Killela, PJ; Pirozzi, CJ; Healy, P; Reitman, ZJ; Lipp, E; Rasheed, BA; Yang, R; Diplas, BH; Wang, Z; Greer, PK; Zhu, H; Wang, CY; Carpenter, AB; Friedman, H; Friedman, AH; Keir, ST; He, J; He, Y; McLendon, RE; Herndon, JE; Yan, H; Bigner, DD
MLA Citation
Killela, PJ, Pirozzi, CJ, Healy, P, Reitman, ZJ, Lipp, E, Rasheed, BA, Yang, R, Diplas, BH, Wang, Z, Greer, PK, Zhu, H, Wang, CY, Carpenter, AB, Friedman, H, Friedman, AH, Keir, ST, He, J, He, Y, McLendon, RE, Herndon, JE, Yan, H, and Bigner, DD. "Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas." Oncotarget 5.6 (March 2014): 1515-1525.
PMID
24722048
Source
epmc
Published In
Oncotarget
Volume
5
Issue
6
Publish Date
2014
Start Page
1515
End Page
1525

Clinico-pathological description of three paediatric medulloblastoma cases with MLL2/3 gene mutations

Authors
Lopez, GY; Grant, GA; Fuchs, HE; Leithe, LG; Gururangan, S; Bigner, DD; Yan, H; McLendon, RE; He, Y
MLA Citation
Lopez, GY, Grant, GA, Fuchs, HE, Leithe, LG, Gururangan, S, Bigner, DD, Yan, H, McLendon, RE, and He, Y. "Clinico-pathological description of three paediatric medulloblastoma cases with MLL2/3 gene mutations." NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY 40.2 (February 2014): 217-220.
Source
wos-lite
Published In
Neuropathology & Applied Neurobiology
Volume
40
Issue
2
Publish Date
2014
Start Page
217
End Page
220
DOI
10.1111/nan.12060

Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma

Chimeric antigen receptors (CAR)-transduced T cells hold great promise in the treatment of malignant disease. Here, we demonstrate that intracerebral injection with a human, epidermal growth factor receptor variant III (EGFRvIII)-specific, third generation CAR successfully treats glioma in mice. Importantly, these results endorse clinical translation of this CAR in patients with EGFRvIII-expressing brain tumors. © 2013 Elsevier Ltd. All rights reserved.

Authors
Choi, BD; Suryadevara, CM; Gedeon, PC; Herndon, JE; Sanchez-Perez, L; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Suryadevara, CM, Gedeon, PC, Herndon, JE, Sanchez-Perez, L, Bigner, DD, and Sampson, JH. "Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma." Journal of Clinical Neuroscience 21.1 (January 1, 2014): 189-190.
Source
scopus
Published In
Journal of Clinical Neuroscience
Volume
21
Issue
1
Publish Date
2014
Start Page
189
End Page
190
DOI
10.1016/j.jocn.2013.03.012

AJAP1 is dysregulated at an early stage of gliomagenesis and suppresses invasion through cytoskeleton reorganization

Aims: Down-regulation of AJAP1 in glioblastoma multiforme (GBM) has been reported. However, the expression profiles of AJAP1 in gliomas and the underlying mechanisms of AJAP1 function on invasion are still poorly understood. Methods: The gene profiles of AJAP1 in glioma patients were studied among four independent cohorts. Confocal imaging was used to analyze the AJAP1 localization. After AJAP1 overexpression in GBM cell lines, cellular polarity, cytoskeleton distribution, and antitumor effect were investigated in vitro and in vivo. Results: AJAP1 expression was significantly decreased in gliomas compared with normal brain in REMBRANDT and CGCA cohorts. Additionally, low AJAP1 expression was associated with worse survival in GBMs in REMBRANDT and TCGA U133A cohorts and was significantly associated with classical and mesenchymal subtypes of GBMs among four cohorts. Confocal imaging indicated AJAP1 localized in cell membranes in low-grade gliomas and AJAP1-overexpressing GBM cells, but difficult to assess in high-grade gliomas due to its absence. AJAP1 overexpression altered the cytoskeleton and cellular polarity in vitro and inhibited the tumor growth in vivo. Conclusions: AJAP1 is dysregulated at an early stage of gliomagenesis and may suppress glioma cell invasion and proliferation, which suggests that AJAP1 may be a potential diagnostic and prognostic marker for gliomas. © 2014 John Wiley & Sons Ltd.

Authors
Han, L; Zhang, KL; Zhang, JX; Zeng, L; Di, CH; Fee, BE; Rivas, M; Bao, ZS; Jiang, T; Bigner, D; Kang, CS; Adamson, DC
MLA Citation
Han, L, Zhang, KL, Zhang, JX, Zeng, L, Di, CH, Fee, BE, Rivas, M, Bao, ZS, Jiang, T, Bigner, D, Kang, CS, and Adamson, DC. "AJAP1 is dysregulated at an early stage of gliomagenesis and suppresses invasion through cytoskeleton reorganization." CNS Neuroscience and Therapeutics 20.5 (January 1, 2014): 429-437.
Source
scopus
Published In
CNS Neuroscience and Therapeutics
Volume
20
Issue
5
Publish Date
2014
Start Page
429
End Page
437
DOI
10.1111/cns.12232

Malignant brainstem gliomas in adults: Clinicopathological characteristics and prognostic factors

Adult malignant brainstem gliomas (BSGs) are poorly characterized due to their relative rarity. We have examined histopathologically confirmed cases of adult malignant BSGs to better characterize the patient and tumor features and outcomes, including the natural history, presentation, imaging, molecular characteristics, prognostic factors, and appropriate treatments. A total of 34 patients were identified, consisting of 22 anaplastic astrocytomas (AAs) and 12 glioblastomas (GBMs). The overall median survival for all patients was 25.8 months, with patients having GBMs experiencing significantly worse survival (12.1 vs. 77.0 months, p = 0.0011). The majority of tumors revealed immunoreactivity for EGFR (93.3 %) and MGMT (64.7 %). Most tumors also exhibited chromosomal abnormalities affecting the loci of epidermal growth factor receptor (92.9 %), MET (100 %), PTEN (61.5 %), and 9p21 (80 %). AAs more commonly appeared diffusely enhancing (50.0 vs. 27.3 %) or diffusely nonenhancing (25.0 vs. 0.0 %), while GBMs were more likely to exhibit focal enhancement (54.6 vs. 10.0 %). Multivariate analysis revealed confirmed histopathology for GBM to significantly affect survival (HR 4.80; 95 % CI 1.86-12.4; p = 0.0012). In conclusion, adult malignant BSGs have an overall poor prognosis, with GBM tumors faring significantly worse than AAs. As AAs and GBMs have differing imaging characteristics, tissue diagnosis may be necessary to accurately determine patient prognosis and identify molecular characteristics which may aid in the treatment of these aggressive tumors. © 2014 Springer Science+Business Media.

Authors
Babu, R; Kranz, PG; Agarwal, V; McLendon, RE; Thomas, S; Friedman, AH; Bigner, DD; Adamson, C
MLA Citation
Babu, R, Kranz, PG, Agarwal, V, McLendon, RE, Thomas, S, Friedman, AH, Bigner, DD, and Adamson, C. "Malignant brainstem gliomas in adults: Clinicopathological characteristics and prognostic factors." Journal of Neuro-Oncology 119.1 (January 1, 2014): 177-185.
Source
scopus
Published In
Journal of Neuro-Oncology
Volume
119
Issue
1
Publish Date
2014
Start Page
177
End Page
185
DOI
10.1007/s11060-014-1471-9

Oncolytic polio virotherapy of cancer

© 2014 American Cancer Society.Recently, the century-old idea of targeting cancer with viruses (oncolytic viruses) has come of age, and promise has been documented in early stage and several late-stage clinical trials in a variety of cancers. Although originally prized for their direct tumor cytotoxicity (oncolytic virotherapy), recently, the proinflammatory and immunogenic effects of viral tumor infection (oncolytic immunotherapy) have come into focus. Indeed, a capacity for eliciting broad, sustained antineoplastic effects stemming from combined direct viral cytotoxicity, innate antiviral activation, stromal proinflammatory stimulation, and recruitment of adaptive immune effector responses is the greatest asset of oncolytic viruses. However, it also is the source for enormous mechanistic complexity that must be considered for successful clinical translation. Because of fundamentally different relationships with their hosts (malignant or not), diverse replication strategies, and distinct modes of tumor cytotoxicity/killing, oncolytic viruses should not be referred to collectively. These agents must be evaluated based on their individual merits. In this review, the authors highlight key mechanistic principles of cancer treatment with the polio:rhinovirus chimera PVSRIPO and their implications for oncolytic immunotherapy in the clinic.

Authors
Brown, MC; Dobrikova, EY; Dobrikov, MI; Walton, RW; Gemberling, SL; Nair, SK; Desjardins, A; Sampson, JH; Friedman, HS; Friedman, AH; Tyler, DS; Bigner, DD; Gromeier, M
MLA Citation
Brown, MC, Dobrikova, EY, Dobrikov, MI, Walton, RW, Gemberling, SL, Nair, SK, Desjardins, A, Sampson, JH, Friedman, HS, Friedman, AH, Tyler, DS, Bigner, DD, and Gromeier, M. "Oncolytic polio virotherapy of cancer." Cancer 120.21 (January 1, 2014): 3277-3286. (Review)
Source
scopus
Published In
Cancer
Volume
120
Issue
21
Publish Date
2014
Start Page
3277
End Page
3286
DOI
10.1002/cncr.28862

EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is uniformly lethal. T-cell-based immunotherapy offers a promising platform for treatment given its potential to specifically target tumor tissue while sparing the normal brain. However, the diffuse and infiltrative nature of these tumors in the brain parenchyma may pose an exceptional hurdle to successful immunotherapy in patients. Areas of invasive tumor are thought to reside behind an intact blood brain barrier, isolating them from effective immunosurveillance and thereby predisposing the development of "immunologically silent" tumor peninsulas. Therefore, it remains unclear if adoptively transferred T cells can migrate to and mediate regression in areas of invasive GBM. One barrier has been the lack of a preclinical mouse model that accurately recapitulates the growth patterns of human GBM in vivo. Here, we demonstrate that D-270 MG xenografts exhibit the classical features of GBM and produce the diffuse and invasive tumors seen in patients. Using this model, we designed experiments to assess whether T cells expressing third-generation chimeric antigen receptors (CARs) targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, would localize to and treat invasive intracerebral GBM. EGFRvIII-targeted CAR (EGFRvIII+ CAR) T cells demonstrated in vitro EGFRvIII antigen-specific recognition and reactivity to the D-270 MG cell line, which naturally expresses EGFRvIII. Moreover, when administered systemically, EGFRvIII+ CAR T cells localized to areas of invasive tumor, suppressed tumor growth, and enhanced survival of mice with established intracranial D-270 MG tumors. Together, these data demonstrate that systemically administered T cells are capable of migrating to the invasive edges of GBM to mediate antitumor efficacy and tumor regression.

Authors
Miao, H; Choi, BD; Suryadevara, CM; Sanchez-Perez, L; Yang, S; De Leon, G; Sayour, EJ; McLendon, R; Herndon, JE; Healy, P; Archer, GE; Bigner, DD; Johnson, LA; Sampson, JH
MLA Citation
Miao, H, Choi, BD, Suryadevara, CM, Sanchez-Perez, L, Yang, S, De Leon, G, Sayour, EJ, McLendon, R, Herndon, JE, Healy, P, Archer, GE, Bigner, DD, Johnson, LA, and Sampson, JH. "EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma." PloS one 9.4 (January 2014): e94281-.
PMID
24722266
Source
epmc
Published In
PloS one
Volume
9
Issue
4
Publish Date
2014
Start Page
e94281
DOI
10.1371/journal.pone.0094281

Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma.

Chimeric antigen receptors (CAR)-transduced T cells hold great promise in the treatment of malignant disease. Here, we demonstrate that intracerebral injection with a human, epidermal growth factor receptor variant III (EGFRvIII)-specific, third generation CAR successfully treats glioma in mice. Importantly, these results endorse clinical translation of this CAR in patients with EGFRvIII-expressing brain tumors.

Authors
Choi, BD; Suryadevara, CM; Gedeon, PC; Herndon, JE; Sanchez-Perez, L; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Suryadevara, CM, Gedeon, PC, Herndon, JE, Sanchez-Perez, L, Bigner, DD, and Sampson, JH. "Intracerebral delivery of a third generation EGFRvIII-specific chimeric antigen receptor is efficacious against human glioma." J Clin Neurosci 21.1 (January 2014): 189-190.
PMID
24054399
Source
pubmed
Published In
Journal of Clinical Neuroscience
Volume
21
Issue
1
Publish Date
2014
Start Page
189
End Page
190
DOI
10.1016/j.jocn.2013.03.012

A novel recombinant immunotoxin-based therapy targeting wild-type and mutant EGFR improves survival in murine models of glioblastoma

Both the amplification of the gene coding for wild-type (wt) epidermal growth factor receptor (EGFR) and the overexpression of the EGFR deletion mutant, commonly known as EGFRvIII, are hallmarks of glioblastoma. We have recently reported a novel, recombinant immunotoxin, D2C7-(scdsFv)-PE38KDEL, that targets both wt EGFR and EGFRvIII, exhibiting potent antineoplastic effects against established murine gliomas. © 2013 Landes Bioscience.

Authors
Chandramohan, V; Bigner, DD
MLA Citation
Chandramohan, V, and Bigner, DD. "A novel recombinant immunotoxin-based therapy targeting wild-type and mutant EGFR improves survival in murine models of glioblastoma." OncoImmunology 2.12 (December 1, 2013): 1-2.
Source
scopus
Published In
OncoImmunology
Volume
2
Issue
12
Publish Date
2013
Start Page
1
End Page
2
DOI
10.4161/onci.26852

Regulatory T cells are redirected to kill glioblastoma by an EGFRviii-targeted bispecific antibody

Regulatory T cells (Tregs) play a central role in in tumor escape from immunosurveillance. We report that a bispecific T-cell engager (BiTE) targeting a mutated form of the epidermal growth factor receptor, i.e., EGFRvIII, potently redirects Tregs to kill glioblastoma through the granzyme-perforin pathway. © 2013 Landes Bioscience.

Authors
Choi, BD; Gedeon, PC; Sanchez-Perez, L; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Sanchez-Perez, L, Bigner, DD, and Sampson, JH. "Regulatory T cells are redirected to kill glioblastoma by an EGFRviii-targeted bispecific antibody." OncoImmunology 2.12 (December 1, 2013): 1-2.
Source
scopus
Published In
OncoImmunology
Volume
2
Issue
12
Publish Date
2013
Start Page
1
End Page
2
DOI
10.4161/onci.26757

A novel recombinant immunotoxin-based therapy targeting wild-type and mutant EGFR improves survival in murine models of glioblastoma.

Both the amplification of the gene coding for wild-type (wt) epidermal growth factor receptor (EGFR) and the overexpression of the EGFR deletion mutant, commonly known as EGFRvIII, are hallmarks of glioblastoma. We have recently reported a novel, recombinant immunotoxin, D2C7-(scdsFv)-PE38KDEL, that targets both wt EGFR and EGFRvIII, exhibiting potent antineoplastic effects against established murine gliomas.

Authors
Chandramohan, V; Bigner, DD
MLA Citation
Chandramohan, V, and Bigner, DD. "A novel recombinant immunotoxin-based therapy targeting wild-type and mutant EGFR improves survival in murine models of glioblastoma." Oncoimmunology 2.12 (December 2013): e26852-.
PMID
24498557
Source
epmc
Published In
OncoImmunology
Volume
2
Issue
12
Publish Date
2013
Start Page
e26852
DOI
10.4161/onci.26852

Regulatory T cells are redirected to kill glioblastoma by an EGFRvIII-targeted bispecific antibody.

Regulatory T cells (Tregs) play a central role in in tumor escape from immunosurveillance. We report that a bispecific T-cell engager (BiTE) targeting a mutated form of the epidermal growth factor receptor, i.e., EGFRvIII, potently redirects Tregs to kill glioblastoma through the granzyme-perforin pathway.

Authors
Choi, BD; Gedeon, PC; Sanchez-Perez, L; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Sanchez-Perez, L, Bigner, DD, and Sampson, JH. "Regulatory T cells are redirected to kill glioblastoma by an EGFRvIII-targeted bispecific antibody." Oncoimmunology 2.12 (December 2013): e26757-.
PMID
24475376
Source
epmc
Published In
OncoImmunology
Volume
2
Issue
12
Publish Date
2013
Start Page
e26757
DOI
10.4161/onci.26757

Proteasome inhibition with bortezomib induces cell death in GBM stem-like cells and temozolomide-resistant glioma cell lines, but stimulates GBM stem-like cells' VEGF production and angiogenesis.

OBJECT: Recurrent malignant gliomas have inherent resistance to traditional chemotherapy. Novel therapies target specific molecular mechanisms involved in abnormal signaling and resistance to apoptosis. The proteasome is a key regulator of multiple cellular functions, and its inhibition in malignant astrocytic lines causes cell growth arrest and apoptotic cell death. The proteasome inhibitor bortezomib was reported to have very good in vitro activity against malignant glioma cell lines, with modest activity in animal models as well as in clinical trials as a single agent. In this paper, the authors describe the multiple effects of bortezomib in both in vitro and in vivo glioma models and offer a novel explanation for its seeming lack of activity. METHODS: Glioma stem-like cells (GSCs) were obtained from resected glioblastomas (GBMs) at surgery and expanded in culture. Stable glioma cell lines (U21 and D54) as well as temozolomide (TMZ)-resistant glioma cells derived from U251 and D54-MG were also cultured. GSCs from 2 different tumors, as well as D54 and U251 cells, were treated with bortezomib, and the effect of the drug was measured using an XTT cell viability assay. The activity of bortezomib was then determined in D54-MG and/or U251 cells using apoptosis analysis as well as caspase-3 activity and proteasome activity measurements. Human glioma xenograft models were created in nude mice by subcutaneous injection. Bevacizumab was administered via intraperitoneal injection at a dose of 5 mg/kg daily. Bortezomib was administered by intraperitoneal injection 1 hour after bevacizumab administration in doses of at a dose of 0.35 mg/kg on days 1, 4, 8, and 11 every 21 days. Tumors were measured twice weekly. RESULTS: Bortezomib induced caspase-3 activation and apoptotic cell death in stable glioma cell lines and in glioma stem-like cells (GSCs) derived from malignant tumor specimens Furthermore, TMZ-resistant glioma cell lines retained susceptibility to the proteasome inhibition. The bortezomib activity was directly proportional with the cells' baseline proteasome activity. The proteasome inhibition stimulated both hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF) production in malignant GSCs. As such, the VEGF produced by GSCs stimulated endothelial cell growth, an effect that could be prevented by the addition of bevacizumab (VEGF antibody) to the media. Similarly, administration of bortezomib and bevacizumab to athymic mice carrying subcutaneous malignant glioma xenografts resulted in greater tumor inhibition and greater improvement in survival than administration of either drug alone. These data indicate that simultaneous proteasome inhibition and VEGF blockade offer increased benefit as a strategy for malignant glioma therapy. CONCLUSIONS: The results of this study indicate that combination therapies based on bortezomib and bevacizumab might offer an increased benefit when the two agents are used in combination. These drugs have a complementary mechanism of action and therefore can be used together to treat TMZ-resistant malignant gliomas.

Authors
Bota, DA; Alexandru, D; Keir, ST; Bigner, D; Vredenburgh, J; Friedman, HS
MLA Citation
Bota, DA, Alexandru, D, Keir, ST, Bigner, D, Vredenburgh, J, and Friedman, HS. "Proteasome inhibition with bortezomib induces cell death in GBM stem-like cells and temozolomide-resistant glioma cell lines, but stimulates GBM stem-like cells' VEGF production and angiogenesis." J Neurosurg 119.6 (December 2013): 1415-1423.
PMID
24093630
Source
pubmed
Published In
Journal of neurosurgery
Volume
119
Issue
6
Publish Date
2013
Start Page
1415
End Page
1423
DOI
10.3171/2013.7.JNS1323

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma.

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.

Authors
Remke, M; Ramaswamy, V; Peacock, J; Shih, DJH; Koelsche, C; Northcott, PA; Hill, N; Cavalli, FMG; Kool, M; Wang, X; Mack, SC; Barszczyk, M; Morrissy, AS; Wu, X; Agnihotri, S; Luu, B; Jones, DTW; Garzia, L; Dubuc, AM; Zhukova, N; Vanner, R; Kros, JM; French, PJ; Van Meir, EG; Vibhakar, R; Zitterbart, K; Chan, JA; Bognár, L; Klekner, A; Lach, B; Jung, S; Saad, AG; Liau, LM; Albrecht, S; Zollo, M; Cooper, MK; Thompson, RC; Delattre, OO; Bourdeaut, F; Doz, FF; Garami, M; Hauser, P; Carlotti, CG et al.
MLA Citation
Remke, M, Ramaswamy, V, Peacock, J, Shih, DJH, Koelsche, C, Northcott, PA, Hill, N, Cavalli, FMG, Kool, M, Wang, X, Mack, SC, Barszczyk, M, Morrissy, AS, Wu, X, Agnihotri, S, Luu, B, Jones, DTW, Garzia, L, Dubuc, AM, Zhukova, N, Vanner, R, Kros, JM, French, PJ, Van Meir, EG, Vibhakar, R, Zitterbart, K, Chan, JA, Bognár, L, Klekner, A, Lach, B, Jung, S, Saad, AG, Liau, LM, Albrecht, S, Zollo, M, Cooper, MK, Thompson, RC, Delattre, OO, Bourdeaut, F, Doz, FF, Garami, M, Hauser, P, and Carlotti, CG et al. "TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma." Acta Neuropathol 126.6 (December 2013): 917-929.
PMID
24174164
Source
pubmed
Published In
Acta Neuropathologica
Volume
126
Issue
6
Publish Date
2013
Start Page
917
End Page
929
DOI
10.1007/s00401-013-1198-2

Recurrence patterns across medulloblastoma subgroups: An integrated clinical and molecular analysis

Background: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. Methods: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. Results: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). Interpretation: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases. Funding: Canadian Institutes of Health Research, National Institutes of Health, Pediatric Brain Tumor Foundation, Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto. © 2013 Elsevier Ltd.

Authors
Ramaswamy, V; Remke, M; Bouffet, E; Faria, CC; Perreault, S; Cho, YJ; Shih, DJ; Luu, B; Dubuc, AM; Northcott, PA; Schüller, U; Gururangan, S; McLendon, R; Bigner, D; Fouladi, M; Ligon, KL; Pomeroy, SL; Dunn, S; Triscott, J; Jabado, N; Fontebasso, A; Jones, DTW; Kool, M; Karajannis, MA; Gardner, SL; Zagzag, D; Nunes, S; Pimentel, J; Mora, J; Lipp, E; Walter, AW; Ryzhova, M; Zheludkova, O; Kumirova, E; Alshami, J; Croul, SE; Rutka, JT; Hawkins, C; Tabori, U; Codispoti, KET; Packer, RJ et al.
MLA Citation
Ramaswamy, V, Remke, M, Bouffet, E, Faria, CC, Perreault, S, Cho, YJ, Shih, DJ, Luu, B, Dubuc, AM, Northcott, PA, Schüller, U, Gururangan, S, McLendon, R, Bigner, D, Fouladi, M, Ligon, KL, Pomeroy, SL, Dunn, S, Triscott, J, Jabado, N, Fontebasso, A, Jones, DTW, Kool, M, Karajannis, MA, Gardner, SL, Zagzag, D, Nunes, S, Pimentel, J, Mora, J, Lipp, E, Walter, AW, Ryzhova, M, Zheludkova, O, Kumirova, E, Alshami, J, Croul, SE, Rutka, JT, Hawkins, C, Tabori, U, Codispoti, KET, and Packer, RJ et al. "Recurrence patterns across medulloblastoma subgroups: An integrated clinical and molecular analysis." The Lancet Oncology 14.12 (November 1, 2013): 1200-1207.
Source
scopus
Published In
The Lancet Oncology
Volume
14
Issue
12
Publish Date
2013
Start Page
1200
End Page
1207
DOI
10.1016/S1470-2045(13)70449-2

KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation.

KMT2D (lysine (K)-specific methyltransferase 2D), formerly named MLL2 (myeloid/lymphoid or mixed-lineage leukemia 2, also known as ALR/MLL4), is a histone methyltransferase that plays an important role in regulating gene transcription. In particular, it targets histone H3 lysine 4 (H3K4), whose methylations serve as a gene activation mark. Recently, KMT2D has emerged as one of the most frequently mutated genes in a variety of cancers and in other human diseases, including lymphoma, medulloblastoma, gastric cancer, and Kabuki syndrome. Mutations in KMT2D identified thus far point to its loss-of-function in pathogenesis and suggest its role as a tumor suppressor in various tissues. To determine the effect of a KMT2D deficiency on neoplastic cells, we used homologous recombination- and nuclease-mediated gene editing approaches to generate a panel of isogenic colorectal and medulloblastoma cancer cell lines that differ with respect to their endogenous KMT2D status. We found that a KMT2D deficiency resulted in attenuated cancer cell proliferation and defective cell migration. Analysis of histone H3 modifications revealed that KMT2D was essential for maintaining the level of global H3K4 monomethylation and that its enzymatic SET domain was directly responsible for this function. Furthermore, we found that a majority of KMT2D binding sites are located in regions of potential enhancer elements. Together, these findings revealed the role of KMT2D in regulating enhancer elements in human cells and shed light on the tumorigenic role of its deficiency. Our study supports that KMT2D has distinct roles in neoplastic cells, as opposed to normal cells, and that inhibiting KMT2D may be a viable strategy for cancer therapeutics.

Authors
Guo, C; Chen, LH; Huang, Y; Chang, C-C; Wang, P; Pirozzi, CJ; Qin, X; Bao, X; Greer, PK; McLendon, RE; Yan, H; Keir, ST; Bigner, DD; He, Y
MLA Citation
Guo, C, Chen, LH, Huang, Y, Chang, C-C, Wang, P, Pirozzi, CJ, Qin, X, Bao, X, Greer, PK, McLendon, RE, Yan, H, Keir, ST, Bigner, DD, and He, Y. "KMT2D maintains neoplastic cell proliferation and global histone H3 lysine 4 monomethylation." Oncotarget 4.11 (November 2013): 2144-2153.
PMID
24240169
Source
pubmed
Published In
Oncotarget
Volume
4
Issue
11
Publish Date
2013
Start Page
2144
End Page
2153
DOI
10.18632/oncotarget.1555

FEASIBILITY AND SAFETY STUDY OF GBM STEM CELL TUMOR AMPLIFIED RNA IMMUNOTHERAPY IN RECURRENT GLIOBLASTOMA

Authors
Vlahovic, G; Desjardins, A; Peters, K; Ranjan, T; Herndon, J; Friedman, A; Friedman, H; Bigner, D; Archer, G; Lally-Goss, D; Sampson, J
MLA Citation
Vlahovic, G, Desjardins, A, Peters, K, Ranjan, T, Herndon, J, Friedman, A, Friedman, H, Bigner, D, Archer, G, Lally-Goss, D, and Sampson, J. "FEASIBILITY AND SAFETY STUDY OF GBM STEM CELL TUMOR AMPLIFIED RNA IMMUNOTHERAPY IN RECURRENT GLIOBLASTOMA." November 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
73
End Page
74

PHASE 1 STUDY OF AN ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) AGAINST RECURRENT GLIOBLASTOMA

Authors
Desjardins, A; Sampson, J; Peters, K; Ranjan, T; Vlahovic, G; Threatt, S; II, HJ; Boulton, S; Lally-Goss, D; McSherry, F; Friedman, A; Friedman, H; Bigner, D; Gromeier, M
MLA Citation
Desjardins, A, Sampson, J, Peters, K, Ranjan, T, Vlahovic, G, Threatt, S, II, HJ, Boulton, S, Lally-Goss, D, McSherry, F, Friedman, A, Friedman, H, Bigner, D, and Gromeier, M. "PHASE 1 STUDY OF AN ONCOLYTIC POLIO/RHINOVIRUS RECOMBINANT (PVSRIPO) AGAINST RECURRENT GLIOBLASTOMA." November 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
107
End Page
108

TARGETING IDH1 MUTATIONS USING PEPTIDE VACCINES IN BRAIN TUMORS

Authors
Reap, E; Archer, G; Sanchez-Perez, L; Norberg, P; Schmittling, R; Nair, S; Cui, X; Snyder, D; Chandramohan, V; Choi, B; Kuan, C-T; Mitchell, D; Bigner, D; Yan, H; Sampson, J
MLA Citation
Reap, E, Archer, G, Sanchez-Perez, L, Norberg, P, Schmittling, R, Nair, S, Cui, X, Snyder, D, Chandramohan, V, Choi, B, Kuan, C-T, Mitchell, D, Bigner, D, Yan, H, and Sampson, J. "TARGETING IDH1 MUTATIONS USING PEPTIDE VACCINES IN BRAIN TUMORS." November 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
71
End Page
71

A BISPECIFIC ANTIBODY REDIRECTS REGULATORY T CELLS TO KILL TUMOR CELLS THROUGH GRANZYME-DEPENDENT CYTOTOXICITY

Authors
Choi, B; Gedeon, PC; Herndon, J; Sanchez-Perez, L; Mitchell, D; Bigner, D; Sampson, J
MLA Citation
Choi, B, Gedeon, PC, Herndon, J, Sanchez-Perez, L, Mitchell, D, Bigner, D, and Sampson, J. "A BISPECIFIC ANTIBODY REDIRECTS REGULATORY T CELLS TO KILL TUMOR CELLS THROUGH GRANZYME-DEPENDENT CYTOTOXICITY." November 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
68
End Page
69

Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis.

BACKGROUND: Recurrent medulloblastoma is a therapeutic challenge because it is almost always fatal. Studies have confirmed that medulloblastoma consists of at least four distinct subgroups. We sought to delineate subgroup-specific differences in medulloblastoma recurrence patterns. METHODS: We retrospectively identified a discovery cohort of all recurrent medulloblastomas at the Hospital for Sick Children (Toronto, ON, Canada) from 1994 to 2012 (cohort 1), and established molecular subgroups using a nanoString-based assay on formalin-fixed paraffin-embedded tissues or frozen tissue. The anatomical site of recurrence (local tumour bed or leptomeningeal metastasis), time to recurrence, and survival after recurrence were assessed in a subgroup-specific manner. Two independent, non-overlapping cohorts (cohort 2: samples from patients with recurrent medulloblastomas from 13 centres worldwide, obtained between 1991 and 2012; cohort 3: samples from patients with recurrent medulloblastoma obtained at the NN Burdenko Neurosurgical Institute [Moscow, Russia] between 1994 and 2011) were analysed to confirm and validate observations. When possible, molecular subgrouping was done on tissue obtained from both the initial surgery and at recurrence. RESULTS: Cohort 1 consisted of 30 patients with recurrent medulloblastomas; nine with local recurrences, and 21 with metastatic recurrences. Cohort 2 consisted of 77 patients and cohort 3 of 96 patients with recurrent medulloblastoma. Subgroup affiliation remained stable at recurrence in all 34 cases with available matched primary and recurrent pairs (five pairs from cohort 1 and 29 pairs from cohort 2 [15 SHH, five group 3, 14 group 4]). This finding was validated in 17 pairs from cohort 3. When analysed in a subgroup-specific manner, local recurrences in cohort 1 were more frequent in SHH tumours (eight of nine [89%]) and metastatic recurrences were more common in group 3 and group 4 tumours (17 of 20 [85%] with one WNT, p=0·0014, local vs metastatic recurrence, SHH vs group 3 vs group 4). The subgroup-specific location of recurrence was confirmed in cohort 2 (p=0·0013 for local vs metastatic recurrence, SHH vs group 3 vs group 4,), and cohort 3 (p<0·0001). Treatment with craniospinal irradiation at diagnosis was not significantly associated with the anatomical pattern of recurrence. Survival after recurrence was significantly longer in patients with group 4 tumours in cohort 1 (p=0·013) than with other subgroups, which was confirmed in cohort 2 (p=0·0075), but not cohort 3 (p=0·70). INTERPRETATION: Medulloblastoma does not change subgroup at the time of recurrence, reinforcing the stability of the four main medulloblastoma subgroups. Significant differences in the location and timing of recurrence across medulloblastoma subgroups have potential treatment ramifications. Specifically, intensified local (posterior fossa) therapy should be tested in the initial treatment of patients with SHH tumours. Refinement of therapy for patients with group 3 or group 4 tumours should focus on metastases.

Authors
Ramaswamy, V; Remke, M; Bouffet, E; Faria, CC; Perreault, S; Cho, Y-J; Shih, DJ; Luu, B; Dubuc, AM; Northcott, PA; Schüller, U; Gururangan, S; McLendon, R; Bigner, D; Fouladi, M; Ligon, KL; Pomeroy, SL; Dunn, S; Triscott, J; Jabado, N; Fontebasso, A; Jones, DTW; Kool, M; Karajannis, MA; Gardner, SL; Zagzag, D; Nunes, S; Pimentel, J; Mora, J; Lipp, E; Walter, AW; Ryzhova, M; Zheludkova, O; Kumirova, E; Alshami, J; Croul, SE; Rutka, JT; Hawkins, C; Tabori, U; Codispoti, K-ET; Packer, RJ et al.
MLA Citation
Ramaswamy, V, Remke, M, Bouffet, E, Faria, CC, Perreault, S, Cho, Y-J, Shih, DJ, Luu, B, Dubuc, AM, Northcott, PA, Schüller, U, Gururangan, S, McLendon, R, Bigner, D, Fouladi, M, Ligon, KL, Pomeroy, SL, Dunn, S, Triscott, J, Jabado, N, Fontebasso, A, Jones, DTW, Kool, M, Karajannis, MA, Gardner, SL, Zagzag, D, Nunes, S, Pimentel, J, Mora, J, Lipp, E, Walter, AW, Ryzhova, M, Zheludkova, O, Kumirova, E, Alshami, J, Croul, SE, Rutka, JT, Hawkins, C, Tabori, U, Codispoti, K-ET, and Packer, RJ et al. "Recurrence patterns across medulloblastoma subgroups: an integrated clinical and molecular analysis." Lancet Oncol 14.12 (November 2013): 1200-1207.
PMID
24140199
Source
pubmed
Published In
The Lancet Oncology
Volume
14
Issue
12
Publish Date
2013
Start Page
1200
End Page
1207
DOI
10.1016/S1470-2045(13)70449-2

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes. © Springer-Verlag Berlin Heidelberg 2013.

Authors
Remke, M; Ramaswamy, V; Peacock, J; Shih, DJH; Koelsche, C; Northcott, PA; Hill, N; Cavalli, FMG; Kool, M; Wang, X; Mack, SC; Barszczyk, M; Morrissy, AS; Wu, X; Agnihotri, S; Luu, B; Jones, DTW; Garzia, L; Dubuc, AM; Zhukova, N; Vanner, R; Kros, JM; French, PJ; Van Meir, EG; Vibhakar, R; Zitterbart, K; Chan, JA; Bognár, L; Klekner, A; Lach, B; Jung, S; Saad, AG; Liau, LM; Albrecht, S; Zollo, M; Cooper, MK; Thompson, RC; Delattre, OO; Bourdeaut, F; Doz, FF; Garami, M; Hauser, P; Carlotti, CG et al.
MLA Citation
Remke, M, Ramaswamy, V, Peacock, J, Shih, DJH, Koelsche, C, Northcott, PA, Hill, N, Cavalli, FMG, Kool, M, Wang, X, Mack, SC, Barszczyk, M, Morrissy, AS, Wu, X, Agnihotri, S, Luu, B, Jones, DTW, Garzia, L, Dubuc, AM, Zhukova, N, Vanner, R, Kros, JM, French, PJ, Van Meir, EG, Vibhakar, R, Zitterbart, K, Chan, JA, Bognár, L, Klekner, A, Lach, B, Jung, S, Saad, AG, Liau, LM, Albrecht, S, Zollo, M, Cooper, MK, Thompson, RC, Delattre, OO, Bourdeaut, F, Doz, FF, Garami, M, Hauser, P, and Carlotti, CG et al. "TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma." Acta Neuropathologica 126.6 (October 31, 2013): 917-929.
Source
scopus
Published In
Acta Neuropathologica
Volume
126
Issue
6
Publish Date
2013
Start Page
917
End Page
929
DOI
10.1007/s00401-013-1198-2

The somatic genomic landscape of glioblastoma.

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

Authors
Brennan, CW; Verhaak, RGW; McKenna, A; Campos, B; Noushmehr, H; Salama, SR; Zheng, S; Chakravarty, D; Sanborn, JZ; Berman, SH; Beroukhim, R; Bernard, B; Wu, C-J; Genovese, G; Shmulevich, I; Barnholtz-Sloan, J; Zou, L; Vegesna, R; Shukla, SA; Ciriello, G; Yung, WK; Zhang, W; Sougnez, C; Mikkelsen, T; Aldape, K; Bigner, DD; Van Meir, EG; Prados, M; Sloan, A; Black, KL; Eschbacher, J; Finocchiaro, G; Friedman, W; Andrews, DW; Guha, A; Iacocca, M; O'Neill, BP; Foltz, G; Myers, J; Weisenberger, DJ et al.
MLA Citation
Brennan, CW, Verhaak, RGW, McKenna, A, Campos, B, Noushmehr, H, Salama, SR, Zheng, S, Chakravarty, D, Sanborn, JZ, Berman, SH, Beroukhim, R, Bernard, B, Wu, C-J, Genovese, G, Shmulevich, I, Barnholtz-Sloan, J, Zou, L, Vegesna, R, Shukla, SA, Ciriello, G, Yung, WK, Zhang, W, Sougnez, C, Mikkelsen, T, Aldape, K, Bigner, DD, Van Meir, EG, Prados, M, Sloan, A, Black, KL, Eschbacher, J, Finocchiaro, G, Friedman, W, Andrews, DW, Guha, A, Iacocca, M, O'Neill, BP, Foltz, G, Myers, J, and Weisenberger, DJ et al. "The somatic genomic landscape of glioblastoma." Cell 155.2 (October 10, 2013): 462-477.
PMID
24120142
Source
pubmed
Published In
Cell
Volume
155
Issue
2
Publish Date
2013
Start Page
462
End Page
477
DOI
10.1016/j.cell.2013.09.034

The integrated landscape of driver genomic alterations in glioblastoma.

Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention.

Authors
Frattini, V; Trifonov, V; Chan, JM; Castano, A; Lia, M; Abate, F; Keir, ST; Ji, AX; Zoppoli, P; Niola, F; Danussi, C; Dolgalev, I; Porrati, P; Pellegatta, S; Heguy, A; Gupta, G; Pisapia, DJ; Canoll, P; Bruce, JN; McLendon, RE; Yan, H; Aldape, K; Finocchiaro, G; Mikkelsen, T; Privé, GG; Bigner, DD; Lasorella, A; Rabadan, R; Iavarone, A
MLA Citation
Frattini, V, Trifonov, V, Chan, JM, Castano, A, Lia, M, Abate, F, Keir, ST, Ji, AX, Zoppoli, P, Niola, F, Danussi, C, Dolgalev, I, Porrati, P, Pellegatta, S, Heguy, A, Gupta, G, Pisapia, DJ, Canoll, P, Bruce, JN, McLendon, RE, Yan, H, Aldape, K, Finocchiaro, G, Mikkelsen, T, Privé, GG, Bigner, DD, Lasorella, A, Rabadan, R, and Iavarone, A. "The integrated landscape of driver genomic alterations in glioblastoma." Nat Genet 45.10 (October 2013): 1141-1149.
PMID
23917401
Source
pubmed
Published In
Nature Genetics
Volume
45
Issue
10
Publish Date
2013
Start Page
1141
End Page
1149
DOI
10.1038/ng.2734

Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis.

Developments in the field of bispecific antibodies have progressed rapidly in recent years, particularly in their potential role for the treatment of malignant disease. However, manufacturing stable molecules has proven to be costly and time-consuming, which in turn has hampered certain aspects of preclinical evaluation including the unavailability of appropriate "negative" controls. Bispecific molecules (e.g., bispecific tandem scFv) exhibit two specificities, often against a tumor antigen as well as an immune-activation ligand such as CD3. While for IgG antibodies, isotype-matched controls are well accepted, when considering smaller antibody fragments it is not possible to adequately control for their biological activity through the use of archetypal isotypes, which differ dramatically in affinity, size, structure, and design. Here, we demonstrate a method for the rapid production of negative control tandem scFvs through complementarity determining region (CDR) mutagenesis, using a recently described bispecific T-cell engager (BiTE) targeting a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII) as an example. Four independent control constructs were developed by this method through alteration of residues spanning individual CDR domains. Importantly, while target antigen affinity was completely impaired, CD3 binding affinity was conserved in each molecule. These results have a potential to enhance the sophistication by which bispecific antibodies can be evaluated in the preclinical setting and may have broader applications for an array of alternative antibody-derived therapeutic platforms.

Authors
Choi, BD; Gedeon, PC; Kuan, C-T; Sanchez-Perez, L; Archer, GE; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Kuan, C-T, Sanchez-Perez, L, Archer, GE, Bigner, DD, and Sampson, JH. "Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis." J Immunol Methods 395.1-2 (September 30, 2013): 14-20.
PMID
23806556
Source
pubmed
Published In
Journal of Immunological Methods
Volume
395
Issue
1-2
Publish Date
2013
Start Page
14
End Page
20
DOI
10.1016/j.jim.2013.06.003

ADOPTIVE LYMPHOCYTE THERAPY (ALT) PLUS DENDRITIC CELL VACCINATION (DCV) AFTER MYELOABLATIVE (MA) OR NON-MYELOABLATIVE (NMA) CONDITIONING IN PATIENTS WITH RECURRENT CENTRAL PNET (C-PNET)

Authors
Gururangan, S; Grant, GA; Driscoll, T; Archer, G; Sayour, EJ; II, HJE; Friedman, HS; Kurtzberg, J; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Gururangan, S, Grant, GA, Driscoll, T, Archer, G, Sayour, EJ, II, HJE, Friedman, HS, Kurtzberg, J, Bigner, DD, Sampson, JH, and Mitchell, DA. "ADOPTIVE LYMPHOCYTE THERAPY (ALT) PLUS DENDRITIC CELL VACCINATION (DCV) AFTER MYELOABLATIVE (MA) OR NON-MYELOABLATIVE (NMA) CONDITIONING IN PATIENTS WITH RECURRENT CENTRAL PNET (C-PNET)." PEDIATRIC BLOOD & CANCER 60 (September 2013): 13-13.
Source
wos-lite
Published In
Pediatric Blood & Cancer
Volume
60
Publish Date
2013
Start Page
13
End Page
13

Human regulatory T cells kill tumor cells through granzyme-dependent cytotoxicity upon retargeting with a bispecific antibody.

A major mechanism by which human regulatory T cells (T(regs)) have been shown to suppress and kill autologous immune cells is through the granzyme-perforin pathway. However, it is unknown whether T(regs) also possess the capacity to kill tumor cells using similar mechanisms. Bispecific antibodies (bscAbs) have emerged as a promising class of therapeutics that activate T cells against tumor antigens without the need for classical MHC-restricted TCR recognition. Here, we show that a bscAb targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, redirects human CD4(+)CD25(+)FoxP3(+) T(regs) to kill glioblastoma (GBM) cells. This activity was significantly abrogated by inhibitors of the granzyme-perforin pathway. Notably, analyses of human primary GBM also displayed diffuse infiltration of granzyme-expressing FoxP3(+) T cells. Together, these data suggest that despite their known suppressive functions, tumor-infiltrating T(regs) possess potent cytotoxic mechanisms that can be co-opted for efficient tumor cell lysis.

Authors
Choi, BD; Gedeon, PC; Herndon, JE; Archer, GE; Reap, EA; Sanchez-Perez, L; Mitchell, DA; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Herndon, JE, Archer, GE, Reap, EA, Sanchez-Perez, L, Mitchell, DA, Bigner, DD, and Sampson, JH. "Human regulatory T cells kill tumor cells through granzyme-dependent cytotoxicity upon retargeting with a bispecific antibody." Cancer immunology research 1.3 (September 2013): 163-.
PMID
24570975
Source
epmc
Published In
Cancer Immunology Research
Volume
1
Issue
3
Publish Date
2013
Start Page
163
DOI
10.1158/2326-6066.cir-13-0049

Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL, targeting EGFRwt and EGFRvIII for brain tumor therapy.

The EGF receptor gene (EGFR) is most frequently amplified and overexpressed, along with its deletion mutant, EGFRvIII, in glioblastoma. We tested the preclinical efficacy of the recombinant immunotoxin, D2C7-(scdsFv)-PE38KDEL, which is reactive with a 55-amino acid (AA) region present in the extracellular domain of both EGFRwt (583-637 AAs) and EGFRvIII (292-346 AAs) proteins.The binding affinity and specificity of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII were measured by surface-plasmon resonance and flow cytometry. In vitro cytotoxicity of D2C7-(scdsFv)-PE38KDEL was measured by inhibition of protein synthesis in human EGFRwt-transfected NR6 (NR6W), human EGFRvIII-transfected NR6 (NR6M), EGFRwt-overexpressing A431-epidermoid-carcinoma, and glioblastoma xenograft cells (43, D08-0493MG, D2159MG, and D270MG). In vivo antitumor efficacy of D2C7-(scdsFv)-PE38KDEL was evaluated using 43, NR6M, and D270MG orthotopic tumor models.The KD of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII was 1.6×10(-9) mol/L and 1.3×10(-9) mol/L, respectively. Flow cytometry with NR6W and NR6M cells confirmed the specificity of D2C7-(scdsFv)-PE38KDEL for EGFRwt and EGFRvIII. The D2C7-(scdsFv)-PE38KDEL IC50 was 0.18 to 2.5 ng/mL on cells expressing EGFRwt (NR6W, A431, 43, and D08-0493MG). The D2C7-(scdsFv)-PE38KDEL IC50 was approximately 0.25 ng/mL on EGFRvIII-expressing cells (NR6M) and on EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells (D2159MG and D270MG). Significantly, in intracranial tumor models of 43, NR6M, and D270MG, treatment with D2C7-(scdsFv)-PE38KDEL by convection-enhanced delivery prolonged survival by 310% (P=0.006), 28% (P=0.002), and 166% (P=0.001), respectively.In preclinical studies, the D2C7-(scdsFv)-PE38KDEL immunotoxin exhibited significant potential for treating brain tumors expressing EGFRwt, EGFRvIII, or both.

Authors
Chandramohan, V; Bao, X; Keir, ST; Pegram, CN; Szafranski, SE; Piao, H; Wikstrand, CJ; McLendon, RE; Kuan, C-T; Pastan, IH; Bigner, DD
MLA Citation
Chandramohan, V, Bao, X, Keir, ST, Pegram, CN, Szafranski, SE, Piao, H, Wikstrand, CJ, McLendon, RE, Kuan, C-T, Pastan, IH, and Bigner, DD. "Construction of an immunotoxin, D2C7-(scdsFv)-PE38KDEL, targeting EGFRwt and EGFRvIII for brain tumor therapy." Clinical cancer research : an official journal of the American Association for Cancer Research 19.17 (September 2013): 4717-4727.
PMID
23857604
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
19
Issue
17
Publish Date
2013
Start Page
4717
End Page
4727
DOI
10.1158/1078-0432.ccr-12-3891

Affinity-matured recombinant immunotoxin targeting gangliosides 3'-isoLM1 and 3',6'-isoLD1 on malignant gliomas.

About 60 percent of glioblastomas highly express the gangliosides 3'-isoLM1 and 3',6'-isoLD1 on the cell surface, providing ideal targets for brain tumor immunotherapy. A novel recombinant immunotoxin, DmAb14m-(scFv)-PE38KDEL (DmAb14m-IT), specific for the gangliosides 3'-isoLM1 and 3',6'-isoLD1, was constructed with improved affinity and increased cytotoxicity for immunotherapeutic targeting of glioblastoma. We isolated an scFv parental clone from a previously established murine hybridoma, DmAb14, that is specific to both 3'-isoLM1 and 3',6'-isoLD1. We then performed in vitro affinity maturation by CDR hotspot random mutagenesis. The binding affinity and specificity of affinity-matured DmAb14m-IT were measured by surface-plasmon resonance, flow cytometry, and immunohistochemical analysis. In vitro cytotoxicity of DmAb14m-IT was measured by protein synthesis inhibition and cell death assays in human cell lines expressing gangliosides 3'-isoLM1 and 3',6'-isoLD1 (D54MG and D336MG) and xenograft-derived cells (D2224MG). As a result, the KD of DmAb14m-IT for gangliosides 3'-isoLM1 and 3',6'-isoLD1 was 2.6 × 10(-9)M. Also, DmAb14m-IT showed a significantly higher internalization rate in cells expressing 3'-isoLM1 and 3',6'-isoLD1. The DmAb14m-IT IC 50 was 80 ng/mL (1194 pM) on the D54MG cell line, 5 ng/ml (75 pM) on the D336MG cell line, and 0.5 ng/ml (7.5 pM) on the D2224MG xenograft-derived cells. There was no cytotoxicity on ganglioside-negative HEK293 cells. Immunohistochemical analysis confirmed the specific apparent affinity of DmAb14m-IT with 3'-isoLM1 and 3',6'-isoLD1. In conclusion, DmAb14m-IT showed specific binding affinity, a significantly high internalization rate, and selective cytotoxicity on glioma cell lines and xenograft-derived cells expressing 3'-isoLM1 and 3',6'-isoLD1, thereby displaying robust therapeutic potential for testing the antitumor efficacy of DmAb14m-IT at the preclinical level and eventually in the clinical setting.

Authors
Piao, H; Kuan, C-T; Chandramohan, V; Keir, ST; Pegram, CN; Bao, X; Månsson, J-E; Pastan, IH; Bigner, DD
MLA Citation
Piao, H, Kuan, C-T, Chandramohan, V, Keir, ST, Pegram, CN, Bao, X, Månsson, J-E, Pastan, IH, and Bigner, DD. "Affinity-matured recombinant immunotoxin targeting gangliosides 3'-isoLM1 and 3',6'-isoLD1 on malignant gliomas." mAbs 5.5 (September 2013): 748-762.
PMID
23924792
Source
epmc
Published In
mAbs
Volume
5
Issue
5
Publish Date
2013
Start Page
748
End Page
762
DOI
10.4161/mabs.25860

Dose-Finding and Safety Study of an Oncolytic Polio/Rhinovirus Recombinant Against Recurrent Glioblastoma

Authors
Sampson, JH; Desjardins, A; Peters, KB; Ranjan, T; Vlahovic, G; Lally-Goss, D; Threatt, S; Herndon, J; Friedman, AH; Friedman, H; Bigner, D; Gromeier, M
MLA Citation
Sampson, JH, Desjardins, A, Peters, KB, Ranjan, T, Vlahovic, G, Lally-Goss, D, Threatt, S, Herndon, J, Friedman, AH, Friedman, H, Bigner, D, and Gromeier, M. "Dose-Finding and Safety Study of an Oncolytic Polio/Rhinovirus Recombinant Against Recurrent Glioblastoma." August 2013.
Source
wos-lite
Published In
Neurosurgery
Volume
60
Publish Date
2013
Start Page
155
End Page
155

Antibody, T-cell and dendritic cell immunotherapy for malignant brain tumors.

Modest improvement in brain tumor patient survival has been achieved through advances in surgical, adjuvant radiation and chemotherapeutic strategies. However, these traditional approaches have been unsuccessful in permanently controlling these aggressive tumors, with recurrence being quite common. Hence, there is a need for novel therapeutic approaches that specifically target the molecularly diverse brain tumor cell population. The ability of the immune system to recognize altered tumor cells while avoiding surrounding normal cells offers an enormous advantage over the nonspecific nature of the conventional treatment schemes. Therefore, immunotherapy represents a promising approach that may supplement the standard therapies in eliminating the residual brain tumor cells. This review summarizes different immunotherapeutic approaches currently being tested for malignant brain tumor treatment.

Authors
Chandramohan, V; Mitchell, DA; Johnson, LA; Sampson, JH; Bigner, DD
MLA Citation
Chandramohan, V, Mitchell, DA, Johnson, LA, Sampson, JH, and Bigner, DD. "Antibody, T-cell and dendritic cell immunotherapy for malignant brain tumors." Future oncology (London, England) 9.7 (July 2013): 977-990. (Review)
PMID
23837761
Source
epmc
Published In
Future oncology (London, England)
Volume
9
Issue
7
Publish Date
2013
Start Page
977
End Page
990
DOI
10.2217/fon.13.47

An EGFRvIII-targeted bispecific T-cell engager overcomes limitations of the standard of care for glioblastoma.

While advanced surgical techniques, radiation therapy and chemotherapeutic regimens provide a tangible benefit for patients with glioblastoma (GBM), the average survival from the time of diagnosis remains less than 15 months. Current therapy for GBM is limited by the nonspecific nature of treatment, prohibiting therapy that is aggressive and prolonged enough to eliminate all malignant cells. As an alternative, bispecific antibodies can redirect the immune system to eliminate malignant cells with exquisite potency and specificity. We have recently developed an EGF receptor variant III (EGFRvIII)-targeted bispecific antibody that redirects T cells to eliminate EGFRvIII-expressing GBM. The absolute tumor specificity of EGFRvIII and the lack of immunologic crossreactivity with healthy cells allow this therapeutic to overcome limitations associated with the nonspecific nature of the current standard of care for GBM. Evidence indicates that the molecule can exert therapeutically significant effects in the CNS following systemic administration. Additional advantages in terms of ease-of-production and off-the-shelf availability further the clinical utility of this class of therapeutics.

Authors
Gedeon, PC; Choi, BD; Hodges, TR; Mitchell, DA; Bigner, DD; Sampson, JH
MLA Citation
Gedeon, PC, Choi, BD, Hodges, TR, Mitchell, DA, Bigner, DD, and Sampson, JH. "An EGFRvIII-targeted bispecific T-cell engager overcomes limitations of the standard of care for glioblastoma." Expert Rev Clin Pharmacol 6.4 (July 2013): 375-386. (Review)
PMID
23927666
Source
pubmed
Published In
Expert review of clinical pharmacology
Volume
6
Issue
4
Publish Date
2013
Start Page
375
End Page
386
DOI
10.1586/17512433.2013.811806

ENGINEERING RNA NANOPARTICLE VACCINES TO TARGET MALIGNANT PEDIATRIC BRAIN TUMORS

Authors
Sayour, E; Sanchez-Perez, L; Pham, C; Snyder, D; Flores, C; Kemeny, H; Xie, W; Cui, X; Bigner, D; Sampson, J; Mitchell, D
MLA Citation
Sayour, E, Sanchez-Perez, L, Pham, C, Snyder, D, Flores, C, Kemeny, H, Xie, W, Cui, X, Bigner, D, Sampson, J, and Mitchell, D. "ENGINEERING RNA NANOPARTICLE VACCINES TO TARGET MALIGNANT PEDIATRIC BRAIN TUMORS." PEDIATRIC BLOOD & CANCER 60 (June 2013): S4-S4.
Source
wos-lite
Published In
Pediatric Blood & Cancer
Volume
60
Publish Date
2013
Start Page
S4
End Page
S4

Isocitrate dehydrogenase 1: what it means to the neurosurgeon: a review.

Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered to be frequent and highly conserved in secondary glioblastoma multiforme and lower-grade gliomas. Although IDH1 mutations confer a unique genotype that has been associated with a favorable prognosis, the role of the mutated IDH1 enzyme and its metabolites in tumor initiation and maintenance remains unresolved. However, given that IDH1 mutations are homogeneously expressed and are limited solely to tumor tissue, targeting this mutation could potentially yield novel treatment strategies for patients with glioblastoma multiforme.

Authors
Hodges, TR; Choi, BD; Bigner, DD; Yan, H; Sampson, JH
MLA Citation
Hodges, TR, Choi, BD, Bigner, DD, Yan, H, and Sampson, JH. "Isocitrate dehydrogenase 1: what it means to the neurosurgeon: a review." J Neurosurg 118.6 (June 2013): 1176-1180. (Review)
PMID
23581583
Source
pubmed
Published In
Journal of neurosurgery
Volume
118
Issue
6
Publish Date
2013
Start Page
1176
End Page
1180
DOI
10.3171/2013.3.JNS122282

BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide.

B lymphocyte stimulator (BLyS) is a cytokine involved in differentiation and survival of follicular B cells along with humoral response potentiation. Lymphopenia is known to precipitate dramatic elevation in serum BLyS; however, the use of this effect to enhance humoral responses following vaccination has not been evaluated. We evaluated BLyS serum levels and antigen-specific antibody titers in 8 patients undergoing therapeutic temozolomide (TMZ)-induced lymphopenia, with concomitant vaccine against a tumor-specific mutation in the epidermal growth factor receptor (EGFRvIII). Our studies demonstrate that TMZ-induced lymphopenia corresponded with spikes in serum BLyS that directly preceded the induction of anti-EGFRvIII antigen-specific antibody titers, in some cases as high as 1:2,000,000. Our data are the first clinical observation of BLyS serum elevation and greatly enhanced humoral immune responses as a consequence of chemotherapy-induced lymphopenia. These observations should be considered for the development of future vaccination strategies in the setting of malignancy.

Authors
Sanchez-Perez, L; Choi, BD; Reap, EA; Sayour, EJ; Norberg, P; Schmittling, RJ; Archer, GE; Herndon, JE; Mitchell, DA; Heimberger, AB; Bigner, DD; Sampson, JH
MLA Citation
Sanchez-Perez, L, Choi, BD, Reap, EA, Sayour, EJ, Norberg, P, Schmittling, RJ, Archer, GE, Herndon, JE, Mitchell, DA, Heimberger, AB, Bigner, DD, and Sampson, JH. "BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide." Cancer Immunol Immunother 62.6 (June 2013): 983-987.
PMID
23591978
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
62
Issue
6
Publish Date
2013
Start Page
983
End Page
987
DOI
10.1007/s00262-013-1405-y

Phase II trial for patients with newly diagnosed glioblastoma (GBM) treated with carmustine wafers followed by concurrent radiation therapy (RT), temozolomide (TMZ), and bevacizumab (BV), then followed by TMZ and BV post-RT.

Authors
Ranjan, T; Peters, KB; Vlahovic, G; Alderson, LM; Herndon, JE; McSherry, F; Threatt, S; Sampson, JH; Friedman, AH; Bigner, DD; Friedman, HS; Vredenburgh, JJ; Desjardins, A
MLA Citation
Ranjan, T, Peters, KB, Vlahovic, G, Alderson, LM, Herndon, JE, McSherry, F, Threatt, S, Sampson, JH, Friedman, AH, Bigner, DD, Friedman, HS, Vredenburgh, JJ, and Desjardins, A. "Phase II trial for patients with newly diagnosed glioblastoma (GBM) treated with carmustine wafers followed by concurrent radiation therapy (RT), temozolomide (TMZ), and bevacizumab (BV), then followed by TMZ and BV post-RT." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Dose-finding and safety study of an oncolytic polio/rhinovirus recombinant against recurrent glioblastoma.

Authors
Desjardins, A; Sampson, JH; Peters, KB; Ranjan, T; Vlahovic, G; Threatt, S; Herndon, JE; Friedman, AH; Friedman, HS; Bigner, DD; Gromeier, M
MLA Citation
Desjardins, A, Sampson, JH, Peters, KB, Ranjan, T, Vlahovic, G, Threatt, S, Herndon, JE, Friedman, AH, Friedman, HS, Bigner, DD, and Gromeier, M. "Dose-finding and safety study of an oncolytic polio/rhinovirus recombinant against recurrent glioblastoma." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Current immunotherapeutic targets in gliomas

The prospect for high-grade astrocytic tumor patients continues to be dismal, evenwith advances in surgery, radiotherapy, and chemotherapy. There is a need for thedevelopment of novel therapies that would eliminate the heterogeneous and diffuseastrocytic tumor cells.Innovative therapeutic approaches for the treatment of central nervous systemneoplasia, such as antibody-mediated immunotherapeutics, cellular immunotherapeutics,and oncolytic viruses targeting tumor-associated antigens, have emerged during the pastfew years.Herein we review several of the glioma-associated antigens and the current status ofimmunotherapeutics and oncolytic viruses targeting these antigens. © 2013 Nova Science Publishers, Inc. All rights reserved.

Authors
Chandramohan, V; Mitchell, DA; Gromeier, M; Sampson, JH; Bigner, DD
MLA Citation
Chandramohan, V, Mitchell, DA, Gromeier, M, Sampson, JH, and Bigner, DD. "Current immunotherapeutic targets in gliomas." (May 1, 2013): 287-305. (Chapter)
Source
scopus
Publish Date
2013
Start Page
287
End Page
305

Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors.

Our study demonstrates the glioma tumor antigen podoplanin to be present at very high levels (>90%) in both glioblastoma (D2159MG, D08-0308MG and D08-0493MG) and medulloblastoma (D283MED, D425MED and DAOY) xenografts and cell line. We constructed a novel recombinant single-chain antibody variable region fragment (scFv), NZ-1, specific for podoplanin from the NZ-1 hybridoma. NZ-1-scFv was then fused to Pseudomonas exotoxin A, carrying a C-terminal KDEL peptide (NZ-1-PE38KDEL). The immunotoxin (IT) was further stabilized by a disulfide (ds) bond between the heavy-chain and light-chain variable regions as the construct NZ-1-(scdsFv)-PE38KDEL. NZ-1-(scdsFv)-PE38KDEL exhibited significant reactivity to glioblastoma and medulloblastoma cells. The affinity of NZ-1-(scdsFv), NZ-1-(scdsFv)-PE38KDEL and NZ-1 antibody for podoplanin peptide was 2.1 × 10(-8) M, 8.0 × 10(-8) M and 3.9 × 10(-10) M, respectively. In a protein stability assay, NZ-1-(scdsFv)-PE38KDEL retained 33-98% of its activity, whereas that of NZ-1-PE38KDEL declined to 13% of its initial levels after incubation at 37°C for 3 days. In vitro cytotoxicity of the NZ-1-(scdsFv)-PE38KDEL was measured in cells isolated from glioblastoma xenografts, D2159MG, D08-0308MG and D08-0493MG, and in the medulloblastoma D283MED, D425MED and DOAY xenografts and cell line. The NZ-1-(scdsFv)-PE38KDEL IT was highly cytotoxic, with an 50% inhibitory concentration in the range of 1.6-29 ng/ml. Significantly, NZ-1-(scdsFv)-PE38KDEL demonstrated tumor growth delay, averaging 24 days (p < 0.001) and 21 days (p < 0.001) in D2159MG and D283MED in vivo tumor models, respectively. Crucially, in the D425MED intracranial tumor model, NZ-1-(scdsFv)-PE38KDEL caused a 41% increase in survival (p ≤ 0.001). In preclinical studies, NZ-1-(scdsFv)-PE38KDEL exhibited significant potential as a targeting agent for malignant brain tumors.

Authors
Chandramohan, V; Bao, X; Kato Kaneko, M; Kato, Y; Keir, ST; Szafranski, SE; Kuan, C-T; Pastan, IH; Bigner, DD
MLA Citation
Chandramohan, V, Bao, X, Kato Kaneko, M, Kato, Y, Keir, ST, Szafranski, SE, Kuan, C-T, Pastan, IH, and Bigner, DD. "Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors." International journal of cancer 132.10 (May 2013): 2339-2348.
PMID
23115013
Source
epmc
Published In
International Journal of Cancer
Volume
132
Issue
10
Publish Date
2013
Start Page
2339
End Page
2348
DOI
10.1002/ijc.27919

Abstract 4322: Efficacy of Sym004, a novel anti-EGFR antibody mixture, against EGFRvIII positive glioblastoma xenografts.

Authors
Keir, ST; Roskoski, MA; Kragh, M; Pederson, MW; Jacobsen, HJ; Horak, ID; Friedman, HS; Bigner, DD
MLA Citation
Keir, ST, Roskoski, MA, Kragh, M, Pederson, MW, Jacobsen, HJ, Horak, ID, Friedman, HS, and Bigner, DD. "Abstract 4322: Efficacy of Sym004, a novel anti-EGFR antibody mixture, against EGFRvIII positive glioblastoma xenografts." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
4322
End Page
4322
DOI
10.1158/1538-7445.AM2013-4322

TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.

Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (≥15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.

Authors
Killela, PJ; Reitman, ZJ; Jiao, Y; Bettegowda, C; Agrawal, N; Diaz, LA; Friedman, AH; Friedman, H; Gallia, GL; Giovanella, BC; Grollman, AP; He, T-C; He, Y; Hruban, RH; Jallo, GI; Mandahl, N; Meeker, AK; Mertens, F; Netto, GJ; Rasheed, BA; Riggins, GJ; Rosenquist, TA; Schiffman, M; Shih, I-M; Theodorescu, D; Torbenson, MS; Velculescu, VE; Wang, T-L; Wentzensen, N; Wood, LD; Zhang, M; McLendon, RE; Bigner, DD; Kinzler, KW; Vogelstein, B; Papadopoulos, N; Yan, H
MLA Citation
Killela, PJ, Reitman, ZJ, Jiao, Y, Bettegowda, C, Agrawal, N, Diaz, LA, Friedman, AH, Friedman, H, Gallia, GL, Giovanella, BC, Grollman, AP, He, T-C, He, Y, Hruban, RH, Jallo, GI, Mandahl, N, Meeker, AK, Mertens, F, Netto, GJ, Rasheed, BA, Riggins, GJ, Rosenquist, TA, Schiffman, M, Shih, I-M, Theodorescu, D, Torbenson, MS, Velculescu, VE, Wang, T-L, Wentzensen, N, Wood, LD, Zhang, M, McLendon, RE, Bigner, DD, Kinzler, KW, Vogelstein, B, Papadopoulos, N, and Yan, H. "TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal." Proc Natl Acad Sci U S A 110.15 (April 9, 2013): 6021-6026.
PMID
23530248
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
15
Publish Date
2013
Start Page
6021
End Page
6026
DOI
10.1073/pnas.1303607110

A novel bispecific antibody recruits T cells to eradicate tumors in the "immunologically privileged" central nervous system.

Bispecific T-cell engagers (BiTEs) may break multiple barriers that currently limit the use of immunotherapy in glioblastoma patients. We have recently described a novel BiTE specific for a mutated form of the epidermal growth factor receptor, EGFRvIII, that exerts potent antineoplastic effects against established invasive tumors of the brain.

Authors
Choi, BD; Pastan, I; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Pastan, I, Bigner, DD, and Sampson, JH. "A novel bispecific antibody recruits T cells to eradicate tumors in the "immunologically privileged" central nervous system." Oncoimmunology 2.4 (April 1, 2013): e23639-.
PMID
23734318
Source
pubmed
Published In
OncoImmunology
Volume
2
Issue
4
Publish Date
2013
Start Page
e23639
DOI
10.4161/onci.23639

RNA NANOPARTICLE VACCINES RE-DIRECT HOST-IMMUNITY AGAINST INTRACRANIAL MALIGNANCIES

Authors
Sayour, E; Pham, C; Sanchez-Perez, L; Snyder, D; Flores, C; Kemeny, H; Xie, W; Cui, X; Bigner, D; Sampson, J; Mitchell, D
MLA Citation
Sayour, E, Pham, C, Sanchez-Perez, L, Snyder, D, Flores, C, Kemeny, H, Xie, W, Cui, X, Bigner, D, Sampson, J, and Mitchell, D. "RNA NANOPARTICLE VACCINES RE-DIRECT HOST-IMMUNITY AGAINST INTRACRANIAL MALIGNANCIES." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
36
End Page
36

NOVEL ROLE FOR ENHANCING IMMUNOTHERAPY AGAINST PEDIATRIC BRAIN TUMORS USING HEMATOPOIETIC STEM CELLS

Authors
Flores, C; Pham, C; Snyder, D; Sanchez-Perez, L; Bigner, D; Sampson, J; Mitchell, D
MLA Citation
Flores, C, Pham, C, Snyder, D, Sanchez-Perez, L, Bigner, D, Sampson, J, and Mitchell, D. "NOVEL ROLE FOR ENHANCING IMMUNOTHERAPY AGAINST PEDIATRIC BRAIN TUMORS USING HEMATOPOIETIC STEM CELLS." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
42
End Page
42

ONCOLYTIC POLIOVIRUS IMMUNOTHERAPY OF PRIMARY CNS TUMORS

Authors
Gromeier, M; Desjardins, A; Sampson, JH; Threatt, SJE; Herndon, JE; Friedman, A; Friedman, HS; Bigner, DD
MLA Citation
Gromeier, M, Desjardins, A, Sampson, JH, Threatt, SJE, Herndon, JE, Friedman, A, Friedman, HS, and Bigner, DD. "ONCOLYTIC POLIOVIRUS IMMUNOTHERAPY OF PRIMARY CNS TUMORS." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
20
End Page
20

DEVELOPMENTALLY REGULATED ANTIGENS FOR IMMUNOLOGIC TARGETING OF MEDULLOBLASTOMA SUBTYPES

Authors
Pham, CD; Pei, Y; Flores, C; Snyder, D; Bigner, DD; Sampson, JH; Wechsler-Reya, RJ; Mitchell, DA
MLA Citation
Pham, CD, Pei, Y, Flores, C, Snyder, D, Bigner, DD, Sampson, JH, Wechsler-Reya, RJ, and Mitchell, DA. "DEVELOPMENTALLY REGULATED ANTIGENS FOR IMMUNOLOGIC TARGETING OF MEDULLOBLASTOMA SUBTYPES." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
42
End Page
43

A PHASE I/II STUDY OF ADOPTIVE T-CELL THERAPY (ALT) AND DC VACCINATION (DCV) DURING RECOVERY FROM MYELOABLATIVE CHEMOTHERAPY AND HEMATOPOIETIC STEM CELL TRANSPLANTATION (HDC plus ASCR) OR NON-MYELOABLATIVE CONDITIONING (NMA) IN PATIENTS (PTS) WITH RECURRENT CENTRAL PNETS (RE-MATCH PROTOCOL)

Authors
Gururangan, S; Grant, G; Driscoll, T; Archer, G; Herndon, J; Friedman, H; Kurtzberg, J; Bigner, D; Sampson, J; Mitchell, D
MLA Citation
Gururangan, S, Grant, G, Driscoll, T, Archer, G, Herndon, J, Friedman, H, Kurtzberg, J, Bigner, D, Sampson, J, and Mitchell, D. "A PHASE I/II STUDY OF ADOPTIVE T-CELL THERAPY (ALT) AND DC VACCINATION (DCV) DURING RECOVERY FROM MYELOABLATIVE CHEMOTHERAPY AND HEMATOPOIETIC STEM CELL TRANSPLANTATION (HDC plus ASCR) OR NON-MYELOABLATIVE CONDITIONING (NMA) IN PATIENTS (PTS) WITH RECURRENT CENTRAL PNETS (RE-MATCH PROTOCOL)." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
46
End Page
47

Exomic Sequencing of Four Rare Central Nervous System Tumor Types

Authors
Bettegowda, C; Agrawal, N; Jiao, Y; Wang, Y; Wood, LD; Rodriguez, FJ; Hruban, RH; Gallia, GL; Binder, ZA; Riggins, CJ; Salmasi, V; Riggins, GJ; Reitman, ZJ; Rasheed, A; Keir, S; Shinjo, S; Marie, S; McLendon, R; Jallo, G; Vogelstein, B; Bigner, D; Yan, H; Kinzler, KW; Papadopoulos, N
MLA Citation
Bettegowda, C, Agrawal, N, Jiao, Y, Wang, Y, Wood, LD, Rodriguez, FJ, Hruban, RH, Gallia, GL, Binder, ZA, Riggins, CJ, Salmasi, V, Riggins, GJ, Reitman, ZJ, Rasheed, A, Keir, S, Shinjo, S, Marie, S, McLendon, R, Jallo, G, Vogelstein, B, Bigner, D, Yan, H, Kinzler, KW, and Papadopoulos, N. "Exomic Sequencing of Four Rare Central Nervous System Tumor Types." ONCOTARGET 4.4 (April 2013): 572-583.
PMID
23592488
Source
wos-lite
Published In
Oncotarget
Volume
4
Issue
4
Publish Date
2013
Start Page
572
End Page
583

ABERRANT Otx2 EXPRESSION ENHANCES MIGRATION AND INDUCES ECTOPIC PROLIFERATION OF HINDBRAIN NEURONAL PROGENITOR CELLS

Authors
Wortham, M; Reitman, Z; He, Y; Bigner, D; Yan, H
MLA Citation
Wortham, M, Reitman, Z, He, Y, Bigner, D, and Yan, H. "ABERRANT Otx2 EXPRESSION ENHANCES MIGRATION AND INDUCES ECTOPIC PROLIFERATION OF HINDBRAIN NEURONAL PROGENITOR CELLS." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
2
End Page
2

GLOBAL IDENTIFICATION OF MLL2-TARGETED LOCI REVEALS MLL2'S ROLE IN DIVERSE SIGNALING PATHWAYS

Authors
Guo, C; Chang, C-C; Wortham, M; Chen, L; Kernagis, D; Qin, X; Cho, Y-W; Chi, J-T; Grant, G; McLendon, R; Yan, H; Ge, K; Papadopoulos, N; Bigner, D; He, Y
MLA Citation
Guo, C, Chang, C-C, Wortham, M, Chen, L, Kernagis, D, Qin, X, Cho, Y-W, Chi, J-T, Grant, G, McLendon, R, Yan, H, Ge, K, Papadopoulos, N, Bigner, D, and He, Y. "GLOBAL IDENTIFICATION OF MLL2-TARGETED LOCI REVEALS MLL2'S ROLE IN DIVERSE SIGNALING PATHWAYS." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
9
End Page
9

Reversing the Warburg effect as a treatment for glioblastoma.

Glioblastoma multiforme (GBM), like most cancers, possesses a unique bioenergetic state of aerobic glycolysis known as the Warburg effect. Here, we documented that methylene blue (MB) reverses the Warburg effect evidenced by the increasing of oxygen consumption and reduction of lactate production in GBM cell lines. MB decreases GBM cell proliferation and halts the cell cycle in S phase. Through activation of AMP-activated protein kinase, MB inactivates downstream acetyl-CoA carboxylase and decreases cyclin expression. Structure-activity relationship analysis demonstrated that toluidine blue O, an MB derivative with similar bioenergetic actions, exerts similar action in GBM cell proliferation. In contrast, two other MB derivatives, 2-chlorophenothiazine and promethazine, exert no effect on cellular bioenergetics and do not inhibit GBM cell proliferation. MB inhibits cell proliferation in both temozolomide-sensitive and -insensitive GBM cell lines. In a human GBM xenograft model, a single daily dosage of MB does not activate AMP-activated protein kinase signaling, and no tumor regression was observed. In summary, the current study provides the first in vitro proof of concept that reversal of Warburg effect might be a novel therapy for GBM.

Authors
Poteet, E; Choudhury, GR; Winters, A; Li, W; Ryou, M-G; Liu, R; Tang, L; Ghorpade, A; Wen, Y; Yuan, F; Keir, ST; Yan, H; Bigner, DD; Simpkins, JW; Yang, S-H
MLA Citation
Poteet, E, Choudhury, GR, Winters, A, Li, W, Ryou, M-G, Liu, R, Tang, L, Ghorpade, A, Wen, Y, Yuan, F, Keir, ST, Yan, H, Bigner, DD, Simpkins, JW, and Yang, S-H. "Reversing the Warburg effect as a treatment for glioblastoma." J Biol Chem 288.13 (March 29, 2013): 9153-9164.
PMID
23408428
Source
pubmed
Published In
The Journal of biological chemistry
Volume
288
Issue
13
Publish Date
2013
Start Page
9153
End Page
9164
DOI
10.1074/jbc.M112.440354

Rindopepimut: anti-EGFRvIII peptide vaccine, oncolytic.

Glioblastoma, the most common primary malignant brain tumor, is among the most difficult cancers to treat. Despite the aggressive standard of care, including surgical removal followed by radiotherapy with concomitant and adjuvant chemotherapy, the often sudden onset, diffuse infiltrating nature and highly malignant features of the lesion result in a median overall survival of < 15 months. Currently employed standard- of-care therapy for glioblastoma is nonspecific, leading to premature withdrawal of treatment due to off-target toxicity. Rindopepimut is a peptide-based vaccine that elicits a potent humoral and cellular immune response specifically against cells expressing EGFRvIII, a rearranged, cell-surface tyrosine kinase receptor present exclusively in glioblastoma and other common neoplasms. Several phase I and phase II clinical trials have demonstrated that vaccination with rindopepimut is safe, well tolerated and produces a highly potent immune response that effectively eradicates EGFRvIII-expressing tumor cells, leading to a 73% increase in survival among patients with newly diagnosed glioblastoma. Furthermore, temozolomide-induced lymphopenia enhances the rindopepimut-induced immune response against EGFRvIII, allowing for enhanced vaccination responses in the context of standard-of-care chemotherapy. Rindopepimut is currently undergoing evaluation in a phase III international trial for newly diagnosed glioblastoma and is under clinical investigation for recurrent glioblastoma and pediatric brain stem gliomas.

Authors
Gedeon, PC; Choi, BD; Sampson, JH; Bigner, DD
MLA Citation
Gedeon, PC, Choi, BD, Sampson, JH, and Bigner, DD. "Rindopepimut: anti-EGFRvIII peptide vaccine, oncolytic." Drugs of the future 38.3 (March 2013): 147-155.
PMID
25663738
Source
epmc
Published In
Drugs of the future
Volume
38
Issue
3
Publish Date
2013
Start Page
147
End Page
155

RINDOPEPIMUT Anti-EGFRvIII Peptide Vaccine Oncolytic

Authors
Gedeon, PC; Choi, BD; Sampson, JH; Bigner, DD
MLA Citation
Gedeon, PC, Choi, BD, Sampson, JH, and Bigner, DD. "RINDOPEPIMUT Anti-EGFRvIII Peptide Vaccine Oncolytic." DRUGS OF THE FUTURE 38.3 (March 2013): 147-155.
Source
wos-lite
Published In
Drugs of the future
Volume
38
Issue
3
Publish Date
2013
Start Page
147
End Page
155
DOI
10.1358/dof.2013.038.03.1933992

Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas.

Point mutations at Arg132 of the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase 1 (IDH1) occur frequently in gliomas and result in a gain of function to produce the "oncometabolite" D-2-hydroxyglutarate (D-2HG). The mutated IDH1 allele is usually associated with a wild-type IDH1 allele (heterozygous) in cancer. Here, we identify 2 gliomas that underwent loss of the wild-type IDH1 allele but retained the mutant IDH1 allele following tumor progression from World Health Organization (WHO) grade III anaplastic astrocytomas to WHO grade IV glioblastomas. Intratumoral D-2HG was 14-fold lower in the glioblastomas lacking wild-type IDH1 than in glioblastomas with heterozygous IDH1 mutations. To characterize the contribution of wild-type IDH1 to cancer cell D-2HG production, we established an IDH1-mutated astrocytoma (IMA) cell line from a WHO grade III anaplastic astrocytoma. Disruption of the wild-type IDH1 allele in IMA cells by gene targeting resulted in an 87-fold decrease in cellular D-2HG levels, showing that both wild-type and mutant IDH1 alleles are required for D-2HG production in glioma cells. Expression of wild-type IDH1 was also critical for mutant IDH1-associated D-2HG production in the colorectal cancer cell line HCT116. These insights may aid in the development of therapeutic strategies to target IDH1-mutated cancers.

Authors
Jin, G; Reitman, ZJ; Duncan, CG; Spasojevic, I; Gooden, DM; Rasheed, BA; Yang, R; Lopez, GY; He, Y; McLendon, RE; Bigner, DD; Yan, H
MLA Citation
Jin, G, Reitman, ZJ, Duncan, CG, Spasojevic, I, Gooden, DM, Rasheed, BA, Yang, R, Lopez, GY, He, Y, McLendon, RE, Bigner, DD, and Yan, H. "Disruption of wild-type IDH1 suppresses D-2-hydroxyglutarate production in IDH1-mutated gliomas." Cancer Res 73.2 (January 15, 2013): 496-501.
PMID
23204232
Source
pubmed
Published In
Cancer Research
Volume
73
Issue
2
Publish Date
2013
Start Page
496
End Page
501
DOI
10.1158/0008-5472.CAN-12-2852

Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma.

Bispecific antibodies (bscAbs), particularly those of the bispecific T-cell engager (BiTE) subclass, have been shown to effectively redirect T cells against cancer. Previous efforts to target antigens expressed in both tumors and normal tissues have produced significant toxicity, however. Moreover, like other large molecules, bscAbs may be restricted from entry into the "immunologically privileged" CNS. A tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, is a constitutively activated tyrosine kinase not found in normal tissues but frequently expressed in glioblastomas and many other neoplasms. Because it is localized solely to tumor tissue, EGFRvIII presents an ideal target for immunotherapy. Here we report the preclinical evaluation of an EGFRvIII-targeted BiTE, bscEGFRvIIIxCD3. Our results show that bscEGFRvIIIxCD3 activates T cells to mediate potent and antigen-specific lysis of EGFRvIII-expressing gliomas in vitro (P < 0.001) at exceedingly low concentrations (10 ng/mL) and effector-to-target ratios (2.5:1). Treatment with i.v. bscEGFRvIIIxCD3 yielded extended survival in mice with well-established intracerebral tumors (P < 0.05) and achieved durable complete cure at rates up to 75%. Antitumor efficacy was significantly abrogated on blockade of EGFRvIII binding, demonstrating the need for target antigen specificity both in vitro and in vivo. These results demonstrate that BiTEs can be used to elicit functional antitumor immunity in the CNS, and that peptide blockade of BiTE-mediated activity may greatly enhance the safety profile for antibody-redirected T-cell therapies. Finally, bscEGFRvIIIxCD3 represents a unique advancement in BiTE technology given its exquisite tumor specificity, which enables precise elimination of cancer without the risk of autoimmune toxicity.

Authors
Choi, BD; Kuan, C-T; Cai, M; Archer, GE; Mitchell, DA; Gedeon, PC; Sanchez-Perez, L; Pastan, I; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Kuan, C-T, Cai, M, Archer, GE, Mitchell, DA, Gedeon, PC, Sanchez-Perez, L, Pastan, I, Bigner, DD, and Sampson, JH. "Systemic administration of a bispecific antibody targeting EGFRvIII successfully treats intracerebral glioma." Proc Natl Acad Sci U S A 110.1 (January 2, 2013): 270-275.
PMID
23248284
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
110
Issue
1
Publish Date
2013
Start Page
270
End Page
275
DOI
10.1073/pnas.1219817110

Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model.

Glioblastoma multiforme (GBM) is a devastating disease with a dismal prognosis and a very limited response to treatment. The current standard of care for GBM usually consists of surgery, radiation and chemotherapy with the alkylating agent temozolomide, although resistance to this drug is common. The predominant mechanism of action of temozolomide is methylation of guanine residues although this can be reversed by methylguanine methyltransferase (MGMT) as well as other DNA repair systems. The presence of methylguanine causes abortive DNA synthesis with subsequent apoptosis. This suggests that the closer a particular cell is to S phase when it is exposed to temozolomide the more likely it is to die since repair enzymes will have had less time to reverse the damage. T type calcium channel inhibitors can stop the entry of extracellular calcium that is necessary for transit past the G1/S boundary. As a result, T type calcium channel blockers can slow the growth of cancer cells, but do not generally kill them. Though slowing the growth of cancer cells is important in its own right, it also provides a therapeutic strategy in which a T type channel blocker is administered then withdrawn followed by the administration of temozolomide. We show here that imposing this cell cycle restriction increases the efficacy of subsequently administered temozolomide in immunodeficient mice bearing various human GBM xenograft lines. We also present data that MGMT expressing GBM tumors, which are temozolomide resistant, may be rendered more sensitive by this strategy.

Authors
Keir, ST; Friedman, HS; Reardon, DA; Bigner, DD; Gray, LA
MLA Citation
Keir, ST, Friedman, HS, Reardon, DA, Bigner, DD, and Gray, LA. "Mibefradil, a novel therapy for glioblastoma multiforme: cell cycle synchronization and interlaced therapy in a murine model." J Neurooncol 111.2 (January 2013): 97-102.
PMID
23086436
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
111
Issue
2
Publish Date
2013
Start Page
97
End Page
102
DOI
10.1007/s11060-012-0995-0

The integrated landscape of driver genomic alterations in glioblastoma

Glioblastoma is one of the most challenging forms of cancer to treat. Here we describe a computational platform that integrates the analysis of copy number variations and somatic mutations and unravels the landscape of in-frame gene fusions in glioblastoma. We found mutations with loss of heterozygosity in LZTR1, encoding an adaptor of CUL3-containing E3 ligase complexes. Mutations and deletions disrupt LZTR1 function, which restrains the self renewal and growth of glioma spheres that retain stem cell features. Loss-of-function mutations in CTNND2 target a neural-specific gene and are associated with the transformation of glioma cells along the very aggressive mesenchymal phenotype. We also report recurrent translocations that fuse the coding sequence of EGFR to several partners, with EGFR-SEPT14 being the most frequent functional gene fusion in human glioblastoma. EGFR-SEPT14 fusions activate STAT3 signaling and confer mitogen independence and sensitivity to EGFR inhibition. These results provide insights into the pathogenesis of glioblastoma and highlight new targets for therapeutic intervention. © 2013 Nature America, Inc. All rights reserved.

Authors
Frattini, V; Trifonov, V; Chan, JM; Castano, A; Lia, M; Abate, F; Keir, ST; Ji, AX; Zoppoli, P; Niola, F; al, E
MLA Citation
Frattini, V, Trifonov, V, Chan, JM, Castano, A, Lia, M, Abate, F, Keir, ST, Ji, AX, Zoppoli, P, Niola, F, and al, E. "The integrated landscape of driver genomic alterations in glioblastoma." Nature Genetics 45.10 (2013): 1141-1149.
Source
scival
Published In
Nature Genetics
Volume
45
Issue
10
Publish Date
2013
Start Page
1141
End Page
1149
DOI
10.1038/ng.2734

Myeloablative temozolomide enhances CD8⁺ T-cell responses to vaccine and is required for efficacy against brain tumors in mice.

Temozolomide (TMZ) is an alkylating agent shown to prolong survival in patients with high grade glioma and is routinely used to treat melanoma brain metastases. A prominent side effect of TMZ is induction of profound lymphopenia, which some suggest may be incompatible with immunotherapy. Conversely, it has been proposed that recovery from chemotherapy-induced lymphopenia may actually be exploited to potentiate T-cell responses. Here, we report the first demonstration of TMZ as an immune host-conditioning regimen in an experimental model of brain tumor and examine its impact on antitumor efficacy of a well-characterized peptide vaccine. Our results show that high-dose, myeloablative (MA) TMZ resulted in markedly reduced CD4(+), CD8(+) T-cell and CD4(+)Foxp3(+) TReg counts. Adoptive transfer of naïve CD8(+) T cells and vaccination in this setting led to an approximately 70-fold expansion of antigen-specific CD8(+) T cells over controls. Ex vivo analysis of effector functions revealed significantly enhanced levels of pro-inflammatory cytokine secretion from mice receiving MA TMZ when compared to those treated with a lower lymphodepletive, non-myeloablative (NMA) dose. Importantly, MA TMZ, but not NMA TMZ was uniquely associated with an elevation of endogenous IL-2 serum levels, which we also show was required for optimal T-cell expansion. Accordingly, in a murine model of established intracerebral tumor, vaccination-induced immunity in the setting of MA TMZ-but not lymphodepletive, NMA TMZ-led to significantly prolonged survival. Overall, these results may be used to leverage the side-effects of a clinically-approved chemotherapy and should be considered in future study design of immune-based treatments for brain tumors.

Authors
Sanchez-Perez, LA; Choi, BD; Archer, GE; Cui, X; Flores, C; Johnson, LA; Schmittling, RJ; Snyder, D; Herndon, JE; Bigner, DD; Mitchell, DA; Sampson, JH
MLA Citation
Sanchez-Perez, LA, Choi, BD, Archer, GE, Cui, X, Flores, C, Johnson, LA, Schmittling, RJ, Snyder, D, Herndon, JE, Bigner, DD, Mitchell, DA, and Sampson, JH. "Myeloablative temozolomide enhances CD8⁺ T-cell responses to vaccine and is required for efficacy against brain tumors in mice." PLoS One 8.3 (2013): e59082-.
PMID
23527092
Source
pubmed
Published In
PloS one
Volume
8
Issue
3
Publish Date
2013
Start Page
e59082
DOI
10.1371/journal.pone.0059082

Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors

Our study demonstrates the glioma tumor antigen podoplanin to be present at very high levels (>90%) in both glioblastoma (D2159MG, D08-0308MG and D08-0493MG) and medulloblastoma (D283MED, D425MED and DAOY) xenografts and cell line. We constructed a novel recombinant single-chain antibody variable region fragment (scFv), NZ-1, specific for podoplanin from the NZ-1 hybridoma. NZ-1-scFv was then fused to Pseudomonas exotoxin A, carrying a C-terminal KDEL peptide (NZ-1-PE38KDEL). The immunotoxin (IT) was further stabilized by a disulfide (ds) bond between the heavy-chain and light-chain variable regions as the construct NZ-1-(scdsFv)-PE38KDEL. NZ-1-(scdsFv)-PE38KDEL exhibited significant reactivity to glioblastoma and medulloblastoma cells. The affinity of NZ-1-(scdsFv), NZ-1-(scdsFv)-PE38KDEL and NZ-1 antibody for podoplanin peptide was 2.1 × 10-8 M, 8.0 × 10-8 M and 3.9 × 10-10 M, respectively. In a protein stability assay, NZ-1-(scdsFv)-PE38KDEL retained 33-98% of its activity, whereas that of NZ-1-PE38KDEL declined to 13% of its initial levels after incubation at 37°C for 3 days. In vitro cytotoxicity of the NZ-1-(scdsFv)-PE38KDEL was measured in cells isolated from glioblastoma xenografts, D2159MG, D08-0308MG and D08-0493MG, and in the medulloblastoma D283MED, D425MED and DOAY xenografts and cell line. The NZ-1-(scdsFv)-PE38KDEL IT was highly cytotoxic, with an 50% inhibitory concentration in the range of 1.6-29 ng/ml. Significantly, NZ-1-(scdsFv)-PE38KDEL demonstrated tumor growth delay, averaging 24 days (p < 0.001) and 21 days (p < 0.001) in D2159MG and D283MED in vivo tumor models, respectively. Crucially, in the D425MED intracranial tumor model, NZ-1-(scdsFv)-PE38KDEL caused a 41% increase in survival (p ≤ 0.001). In preclinical studies, NZ-1-(scdsFv)-PE38KDEL exhibited significant potential as a targeting agent for malignant brain tumors. What's new? Podoplanin is a glycoprotein that is overexpressed in several types of malignant tumor, including glioblastoma, medulloblastoma, mesothelioma, and germ-cell tumors. In this study, the authors constructed a novel immunotoxin to target podoplanin, by fusing a monoclonal antibody fragment to exotoxin A from Pseudomonas. In preclinical studies, this immunotoxin, called NZ-1-(scdsFv)-PE38KDEL, increased survival by 41%. Its specificity and high binding affinity allow for specific targeting of tumor cells while avoiding adjacent normal tissue, thereby having the potential to improve survival of patients with brain tumors. Copyright © 2012 UICC.

Authors
Chandramohan, V; Bao, X; Kaneko, MK; Kato, Y; Keir, ST; Szafranski, SE; Kuan, CT; Pastan, IH; Bigner, DD
MLA Citation
Chandramohan, V, Bao, X, Kaneko, MK, Kato, Y, Keir, ST, Szafranski, SE, Kuan, CT, Pastan, IH, and Bigner, DD. "Recombinant anti-podoplanin (NZ-1) immunotoxin for the treatment of malignant brain tumors." International Journal of Cancer 132.10 (2013): 2339-2348.
Source
scival
Published In
International Journal of Cancer
Volume
132
Issue
10
Publish Date
2013
Start Page
2339
End Page
2348
DOI
10.1002/ijc.27919

BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide

B lymphocyte stimulator (BLyS) is a cytokine involved in differentiation and survival of follicular B cells along with humoral response potentiation. Lymphopenia is known to precipitate dramatic elevation in serum BLyS; however, the use of this effect to enhance humoral responses following vaccination has not been evaluated. We evaluated BLyS serum levels and antigen-specific antibody titers in 8 patients undergoing therapeutic temozolomide (TMZ)-induced lymphopenia, with concomitant vaccine against a tumor-specific mutation in the epidermal growth factor receptor (EGFRvIII). Our studies demonstrate that TMZ-induced lymphopenia corresponded with spikes in serum BLyS that directly preceded the induction of anti-EGFRvIII antigen-specific antibody titers, in some cases as high as 1:2,000,000. Our data are the first clinical observation of BLyS serum elevation and greatly enhanced humoral immune responses as a consequence of chemotherapy-induced lymphopenia. These observations should be considered for the development of future vaccination strategies in the setting of malignancy. © 2013 Springer-Verlag Berlin Heidelberg.

Authors
Sanchez-Perez, L; Choi, BD; Reap, EA; Sayour, EJ; Norberg, P; Schmittling, RJ; Archer, GE; II, JEH; Mitchell, DA; Heimberger, AB; Bigner, DD; Sampson, JH
MLA Citation
Sanchez-Perez, L, Choi, BD, Reap, EA, Sayour, EJ, Norberg, P, Schmittling, RJ, Archer, GE, II, JEH, Mitchell, DA, Heimberger, AB, Bigner, DD, and Sampson, JH. "BLyS levels correlate with vaccine-induced antibody titers in patients with glioblastoma lymphodepleted by therapeutic temozolomide." Cancer Immunology, Immunotherapy 62.6 (2013): 983-987.
Source
scival
Published In
Cancer Immunology, Immunotherapy
Volume
62
Issue
6
Publish Date
2013
Start Page
983
End Page
987
DOI
10.1007/s00262-013-1405-y

Mibefradil, a novel therapy for glioblastoma multiforme: Cell cycle synchronization and interlaced therapy in a murine model

Glioblastoma multiforme (GBM) is a devastating disease with a dismal prognosis and a very limited response to treatment. The current standard of care for GBM usually consists of surgery, radiation and chemotherapy with the alkylating agent temozolomide, although resistance to this drug is common. The predominant mechanism of action of temozolomide is methylation of guanine residues although this can be reversed by methylguanine methyltransferase (MGMT) as well as other DNA repair systems. The presence of methylguanine causes abortive DNA synthesis with subsequent apoptosis. This suggests that the closer a particular cell is to S phase when it is exposed to temozolomide the more likely it is to die since repair enzymes will have had less time to reverse the damage. T type calcium channel inhibitors can stop the entry of extracellular calcium that is necessary for transit past the G1/S boundary. As a result, T type calcium channel blockers can slow the growth of cancer cells, but do not generally kill them. Though slowing the growth of cancer cells is important in its own right, it also provides a therapeutic strategy in which a T type channel blocker is administered then withdrawn followed by the administration of temozolomide. We show here that imposing this cell cycle restriction increases the efficacy of subsequently administered temozolomide in immunodeficient mice bearing various human GBM xenograft lines. We also present data that MGMT expressing GBM tumors, which are temozolomide resistant, may be rendered more sensitive by this strategy. © 2012 Springer Science+Business Media New York.

Authors
Keir, ST; Friedman, HS; Reardon, DA; Bigner, DD; Gray, LA
MLA Citation
Keir, ST, Friedman, HS, Reardon, DA, Bigner, DD, and Gray, LA. "Mibefradil, a novel therapy for glioblastoma multiforme: Cell cycle synchronization and interlaced therapy in a murine model." Journal of Neuro-Oncology 111.2 (2013): 97-102.
Source
scival
Published In
Journal of Neuro-Oncology
Volume
111
Issue
2
Publish Date
2013
Start Page
97
End Page
102
DOI
10.1007/s11060-012-0995-0

Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis

Developments in the field of bispecific antibodies have progressed rapidly in recent years, particularly in their potential role for the treatment of malignant disease. However, manufacturing stable molecules has proven to be costly and time-consuming, which in turn has hampered certain aspects of preclinical evaluation including the unavailability of appropriate "negative" controls. Bispecific molecules (e.g., bispecific tandem scFv) exhibit two specificities, often against a tumor antigen as well as an immune-activation ligand such as CD3. While for IgG antibodies, isotype-matched controls are well accepted, when considering smaller antibody fragments it is not possible to adequately control for their biological activity through the use of archetypal isotypes, which differ dramatically in affinity, size, structure, and design. Here, we demonstrate a method for the rapid production of negative control tandem scFvs through complementarity determining region (CDR) mutagenesis, using a recently described bispecific T-cell engager (BiTE) targeting a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII) as an example. Four independent control constructs were developed by this method through alteration of residues spanning individual CDR domains. Importantly, while target antigen affinity was completely impaired, CD3 binding affinity was conserved in each molecule. These results have a potential to enhance the sophistication by which bispecific antibodies can be evaluated in the preclinical setting and may have broader applications for an array of alternative antibody-derived therapeutic platforms. © 2013 Elsevier B.V.

Authors
Choi, BD; Gedeon, PC; Kuan, CT; Sanchez-Perez, L; Archer, GE; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Gedeon, PC, Kuan, CT, Sanchez-Perez, L, Archer, GE, Bigner, DD, and Sampson, JH. "Rational design and generation of recombinant control reagents for bispecific antibodies through CDR mutagenesis." Journal of Immunological Methods 395.1-2 (2013): 14-20.
Source
scival
Published In
Journal of Immunological Methods
Volume
395
Issue
1-2
Publish Date
2013
Start Page
14
End Page
20
DOI
10.1016/j.jim.2013.06.003

Induction of the unfolded protein response drives enhanced metabolism and chemoresistance in glioma cells.

The unfolded protein response (UPR) is an endoplasmic reticulum (ER)-based cytoprotective mechanism acting to prevent pathologies accompanying protein aggregation. It is frequently active in tumors, but relatively unstudied in gliomas. We hypothesized that UPR stress effects on glioma cells might protect tumors from additional exogenous stress (ie, chemotherapeutics), postulating that protection was concurrent with altered tumor cell metabolism. Using human brain tumor cell lines, xenograft tumors, human samples and gene expression databases, we determined molecular features of glioma cell UPR induction/activation, and here report a detailed analysis of UPR transcriptional/translational/metabolic responses. Immunohistochemistry, Western and Northern blots identified elevated levels of UPR transcription factors and downstream ER chaperone targets in gliomas. Microarray profiling revealed distinct regulation of stress responses between xenograft tumors and parent cell lines, with gene ontology and network analyses linking gene expression to cell survival and metabolic processes. Human glioma samples were examined for levels of the ER chaperone GRP94 by immunohistochemistry and for other UPR components by Western blotting. Gene and protein expression data from patient gliomas correlated poor patient prognoses with increased expression of ER chaperones, UPR target genes, and metabolic enzymes (glycolysis and lipogenesis). NMR-based metabolomic studies revealed increased metabolic outputs in glucose uptake with elevated glycolytic activity as well as increased phospholipid turnover. Elevated levels of amino acids, antioxidants, and cholesterol were also evident upon UPR stress; in particular, recurrent tumors had overall higher lipid outputs and elevated specific UPR arms. Clonogenicity studies following temozolomide treatment of stressed or unstressed cells demonstrated UPR-induced chemoresistance. Our data characterize the UPR in glioma cells and human tumors, and link the UPR to chemoresistance possibly via enhanced metabolism. Given the role of the UPR in the balance between cell survival and apoptosis, targeting the UPR and/or controlling metabolic activity may prove beneficial for malignant glioma therapeutics.

Authors
Epple, LM; Dodd, RD; Merz, AL; Dechkovskaia, AM; Herring, M; Winston, BA; Lencioni, AM; Russell, RL; Madsen, H; Nega, M; Dusto, NL; White, J; Bigner, DD; Nicchitta, CV; Serkova, NJ; Graner, MW
MLA Citation
Epple, LM, Dodd, RD, Merz, AL, Dechkovskaia, AM, Herring, M, Winston, BA, Lencioni, AM, Russell, RL, Madsen, H, Nega, M, Dusto, NL, White, J, Bigner, DD, Nicchitta, CV, Serkova, NJ, and Graner, MW. "Induction of the unfolded protein response drives enhanced metabolism and chemoresistance in glioma cells. (Published online)" PLoS One 8.8 (2013): e73267-.
PMID
24039668
Source
pubmed
Published In
PloS one
Volume
8
Issue
8
Publish Date
2013
Start Page
e73267
DOI
10.1371/journal.pone.0073267

Convection enhanced delivery of macromolecules for brain tumors.

The blood brain barrier (BBB) poses a significant challenge for drug delivery of macromolecules into the brain. Convection-enhanced delivery (CED) circumvents the BBB through direct intracerebral infusion using a hydrostatic pressure gradient to transfer therapeutic compounds. The efficacy of CED is dependent on the distribution of the therapeutic agent to the targeted region. Here we present a review of convection enhanced delivery of macromolecules, emphasizing the role of tracers in enabling effective delivery anddiscuss current challenges in the field.

Authors
Mehta, AI; Choi, BD; Ajay, D; Raghavan, R; Brady, M; Friedman, AH; Pastan, I; Bigner, DD; Sampson, JH
MLA Citation
Mehta, AI, Choi, BD, Ajay, D, Raghavan, R, Brady, M, Friedman, AH, Pastan, I, Bigner, DD, and Sampson, JH. "Convection enhanced delivery of macromolecules for brain tumors." Curr Drug Discov Technol 9.4 (December 2012): 305-310.
PMID
22339074
Source
pubmed
Published In
Current drug discovery technologies
Volume
9
Issue
4
Publish Date
2012
Start Page
305
End Page
310

A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation.

Monoallelic point mutations of the NADP(+)-dependent isocitrate dehydrogenases IDH1 and IDH2 occur frequently in gliomas, acute myeloid leukemias, and chondromas, and display robust association with specific DNA hypermethylation signatures. Here we show that heterozygous expression of the IDH1(R132H) allele is sufficient to induce the genome-wide alterations in DNA methylation characteristic of these tumors. Using a gene-targeting approach, we knocked-in a single copy of the most frequently observed IDH1 mutation, R132H, into a human cancer cell line and profiled changes in DNA methylation at over 27,000 CpG dinucleotides relative to wild-type parental cells. We find that IDH1(R132H/WT) mutation induces widespread alterations in DNA methylation, including hypermethylation of 2010 and hypomethylation of 842 CpG loci. We demonstrate that many of these alterations are consistent with those observed in IDH1-mutant and G-CIMP+ primary gliomas and can segregate IDH wild-type and mutated tumors as well as those exhibiting the G-CIMP phenotype in unsupervised analysis of two primary glioma cohorts. Further, we show that the direction of IDH1(R132H/WT)-mediated DNA methylation change is largely dependent upon preexisting DNA methylation levels, resulting in depletion of moderately methylated loci. Additionally, whereas the levels of multiple histone H3 and H4 methylation modifications were globally increased, consistent with broad inhibition of histone demethylation, hypermethylation at H3K9 in particular accompanied locus-specific DNA hypermethylation at several genes down-regulated in IDH1(R132H/WT) knock-in cells. These data provide insight on epigenetic alterations induced by IDH1 mutations and support a causal role for IDH1(R132H/WT) mutants in driving epigenetic instability in human cancer cells.

Authors
Duncan, CG; Barwick, BG; Jin, G; Rago, C; Kapoor-Vazirani, P; Powell, DR; Chi, J-T; Bigner, DD; Vertino, PM; Yan, H
MLA Citation
Duncan, CG, Barwick, BG, Jin, G, Rago, C, Kapoor-Vazirani, P, Powell, DR, Chi, J-T, Bigner, DD, Vertino, PM, and Yan, H. "A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation." Genome Res 22.12 (December 2012): 2339-2355.
PMID
22899282
Source
pubmed
Published In
Genome research
Volume
22
Issue
12
Publish Date
2012
Start Page
2339
End Page
2355
DOI
10.1101/gr.132738.111

Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy.

Glioblastomas shed large quantities of small, membrane-bound microvesicles into the circulation. Although these hold promise as potential biomarkers of therapeutic response, their identification and quantification remain challenging. Here, we describe a highly sensitive and rapid analytical technique for profiling circulating microvesicles directly from blood samples of patients with glioblastoma. Microvesicles, introduced onto a dedicated microfluidic chip, are labeled with target-specific magnetic nanoparticles and detected by a miniaturized nuclear magnetic resonance system. Compared with current methods, this integrated system has a much higher detection sensitivity and can differentiate glioblastoma multiforme (GBM) microvesicles from nontumor host cell-derived microvesicles. We also show that circulating GBM microvesicles can be used to analyze primary tumor mutations and as a predictive metric of treatment-induced changes. This platform could provide both an early indicator of drug efficacy and a potential molecular stratifier for human clinical trials.

Authors
Shao, H; Chung, J; Balaj, L; Charest, A; Bigner, DD; Carter, BS; Hochberg, FH; Breakefield, XO; Weissleder, R; Lee, H
MLA Citation
Shao, H, Chung, J, Balaj, L, Charest, A, Bigner, DD, Carter, BS, Hochberg, FH, Breakefield, XO, Weissleder, R, and Lee, H. "Protein typing of circulating microvesicles allows real-time monitoring of glioblastoma therapy." Nat Med 18.12 (December 2012): 1835-1840.
PMID
23142818
Source
pubmed
Published In
Nature Medicine
Volume
18
Issue
12
Publish Date
2012
Start Page
1835
End Page
1840
DOI
10.1038/nm.2994

Enzyme redesign guided by cancer-derived IDH1 mutations.

Mutations in an enzyme can result in a neomorphic catalytic activity in cancers. We applied cancer-associated mutations from isocitrate dehydrogenases to homologous residues in the active sites of homoisocitrate dehydrogenases to derive enzymes that catalyze the conversion of 2-oxoadipate to (R)-2-hydroxyadipate, a critical step for adipic acid production. Thus, we provide a prototypic example of how insights from cancer genome sequencing and functional studies can aid in enzyme redesign.

Authors
Reitman, ZJ; Choi, BD; Spasojevic, I; Bigner, DD; Sampson, JH; Yan, H
MLA Citation
Reitman, ZJ, Choi, BD, Spasojevic, I, Bigner, DD, Sampson, JH, and Yan, H. "Enzyme redesign guided by cancer-derived IDH1 mutations." Nat Chem Biol 8.11 (November 2012): 887-889.
PMID
23001033
Source
pubmed
Published In
Nature Chemical Biology
Volume
8
Issue
11
Publish Date
2012
Start Page
887
End Page
889
DOI
10.1038/nchembio.1065

Mechanism of anti-glioma activity and in vivo efficacy of the cannabinoid ligand KM-233.

Glioblastoma multiforme (GBM) is the most common and devastating form of primary central nervous system malignancy. The prognosis for patients diagnosed with GBM is poor, having a median survival rate of 12-15 months. Despite modern advances in the development of antineoplastic agents, the efficacy of newer anti-cancer agents in the treatment of GBM is yet to be determined. Thus, there remains a significant unmet need for new therapeutic strategies against GBM. A promising chemotherapeutic intervention has emerged from studies of cannabinoid receptor agonists wherein tetrahydrocannabinol has been the most extensively studied. The novel cannabinoid ligand KM-233 was developed as a lead platform for future optimization of biopharmaceutical properties of classical based cannabinoid ligands. Treatment of U87MG human GBM cells with KM-233 caused a time dependent change in the phosphorylation profiles of MEK, ERK1/2, Akt, BAD, STAT3, and p70S6K. Almost complete mitochondrial depolarization was observed 6 h post-treatment followed by a rapid increase in cleaved caspase 3 and significant cytoskeletal contractions. Treatment with KM-233 also resulted in a redistribution of the Golgi-endoplasmic reticulum structures. Dose escalation studies in the orthotopic model using U87MG cells revealed an 80 % reduction in tumor size after 12 mg/kg daily dosing for 20 days. The evaluation of KM-233 against primary tumor tissue in the side flank model revealed a significant decrease in the rate of tumor growth. These findings indicate that structural refinement of KM-233 to improve its biopharmaceutical properties may lead to a novel and efficacious treatment for GBM.

Authors
Gurley, SN; Abidi, AH; Allison, P; Guan, P; Duntsch, C; Robertson, JH; Kosanke, SD; Keir, ST; Bigner, DD; Elberger, AJ; Moore, BM
MLA Citation
Gurley, SN, Abidi, AH, Allison, P, Guan, P, Duntsch, C, Robertson, JH, Kosanke, SD, Keir, ST, Bigner, DD, Elberger, AJ, and Moore, BM. "Mechanism of anti-glioma activity and in vivo efficacy of the cannabinoid ligand KM-233." J Neurooncol 110.2 (November 2012): 163-177.
PMID
22875710
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
110
Issue
2
Publish Date
2012
Start Page
163
End Page
177
DOI
10.1007/s11060-012-0958-5

Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways.

Myeloid/lymphoid or mixed-lineage leukemia (MLL)-family genes encode histone lysine methyltransferases that play important roles in epigenetic regulation of gene transcription. MLL genes are frequently mutated in human cancers. Unlike MLL1, MLL2 (also known as ALR/MLL4) and its homolog MLL3 are not well-understood. Specifically, little is known regarding the extent of global MLL2 involvement in the regulation of gene expression and the mechanism underlying its alterations in driving tumorigenesis. Here we profile the global loci targeted by MLL2. A combinatorial analysis of the MLL2 binding profile and gene expression in MLL2 wild-type versus MLL2-null isogenic cell lines identified direct transcriptional target genes and revealed the connection of MLL2 to multiple cellular signaling pathways, including the p53 pathway, cAMP-mediated signaling, and cholestasis signaling. In particular, we demonstrate that MLL2 participates in retinoic acid receptor signaling by promoting retinoic acid-responsive gene transcription. Our results present a genome-wide integrative analysis of the MLL2 target loci and suggest potential mechanisms underlying tumorigenesis driven by MLL2 alterations.

Authors
Guo, C; Chang, C-C; Wortham, M; Chen, LH; Kernagis, DN; Qin, X; Cho, Y-W; Chi, J-T; Grant, GA; McLendon, RE; Yan, H; Ge, K; Papadopoulos, N; Bigner, DD; He, Y
MLA Citation
Guo, C, Chang, C-C, Wortham, M, Chen, LH, Kernagis, DN, Qin, X, Cho, Y-W, Chi, J-T, Grant, GA, McLendon, RE, Yan, H, Ge, K, Papadopoulos, N, Bigner, DD, and He, Y. "Global identification of MLL2-targeted loci reveals MLL2's role in diverse signaling pathways." Proc Natl Acad Sci U S A 109.43 (October 23, 2012): 17603-17608.
PMID
23045699
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
109
Issue
43
Publish Date
2012
Start Page
17603
End Page
17608
DOI
10.1073/pnas.1208807109

Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients.

BACKGROUND: Bevacizumab improves outcome for most recurrent glioblastoma patients, but the duration of benefit is limited and survival after initial bevacizumab progression is poor. We evaluated bevacizumab continuation beyond initial progression among recurrent glioblastoma patients as it is a common, yet unsupported practice in some countries. METHODS: We analysed outcome among all patients (n=99) who received subsequent therapy after progression on one of five consecutive, single-arm, phase II clinical trials evaluating bevacizumab regimens for recurrent glioblastoma. Of note, the five trials contained similar eligibility, treatment and assessment criteria, and achieved comparable outcome. RESULTS: The median overall survival (OS) and OS at 6 months for patients who continued bevacizumab therapy (n=55) were 5.9 months (95% confidence interval (CI): 4.4, 7.6) and 49.2% (95% CI: 35.2, 61.8), compared with 4.0 months (95% CI: 2.1, 5.4) and 29.5% (95% CI: 17.0, 43.2) for patients treated with a non-bevacizumab regimen (n=44; P=0.014). Bevacizumab continuation was an independent predictor of improved OS (hazard ratio=0.64; P=0.04). CONCLUSION: The results of our retrospective pooled analysis suggest that bevacizumab continuation beyond initial progression modestly improves survival compared with available non-bevacizumab therapy for recurrent glioblastoma patients require evaluation in an appropriately randomised, prospective trial.

Authors
Reardon, DA; Herndon, JE; Peters, KB; Desjardins, A; Coan, A; Lou, E; Sumrall, AL; Turner, S; Lipp, ES; Sathornsumetee, S; Rich, JN; Sampson, JH; Friedman, AH; Boulton, ST; Bigner, DD; Friedman, HS; Vredenburgh, JJ
MLA Citation
Reardon, DA, Herndon, JE, Peters, KB, Desjardins, A, Coan, A, Lou, E, Sumrall, AL, Turner, S, Lipp, ES, Sathornsumetee, S, Rich, JN, Sampson, JH, Friedman, AH, Boulton, ST, Bigner, DD, Friedman, HS, and Vredenburgh, JJ. "Bevacizumab continuation beyond initial bevacizumab progression among recurrent glioblastoma patients." Br J Cancer 107.9 (October 23, 2012): 1481-1487.
PMID
23037712
Source
pubmed
Published In
British Journal of Cancer
Volume
107
Issue
9
Publish Date
2012
Start Page
1481
End Page
1487
DOI
10.1038/bjc.2012.415

FEASIBILITY OF AMPLIFIED CD133((+)) BRAIN TUMOR STEM CELL RNA-PULSED DENDRITIC CELLS FOR THE TREATMENT OF PATIENTS WITH RECURRENT GLIOBLASTOMA

Authors
Archer, GE; Xie, W; Norberg, P; Dechkovskaia, A; Friedman, A; Bigner, DD; Mitchell, DA; Sampson, JH; Boczkowski, D
MLA Citation
Archer, GE, Xie, W, Norberg, P, Dechkovskaia, A, Friedman, A, Bigner, DD, Mitchell, DA, Sampson, JH, and Boczkowski, D. "FEASIBILITY OF AMPLIFIED CD133((+)) BRAIN TUMOR STEM CELL RNA-PULSED DENDRITIC CELLS FOR THE TREATMENT OF PATIENTS WITH RECURRENT GLIOBLASTOMA." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
49
End Page
49

ASSESSMENT OF INTRATUMORAL TREGS AND CLINICAL OUTCOMES IN PRIMARY AND RECURRENT GLIOBLASTOMA

Authors
Sayour, EJ; McLendon, P; Reynolds, R; Bigner, DD; Sampson, JH; McLendon, R; Mitchell, DA
MLA Citation
Sayour, EJ, McLendon, P, Reynolds, R, Bigner, DD, Sampson, JH, McLendon, R, and Mitchell, DA. "ASSESSMENT OF INTRATUMORAL TREGS AND CLINICAL OUTCOMES IN PRIMARY AND RECURRENT GLIOBLASTOMA." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
39
End Page
39

NEWLY DIAGNOSED GLIOBLASTOMA TREATED WITH GLIADEL (R) FOLLOWED BY RADIATION THERAPY (RT), TEMOZOLOMIDE AND BEVACIZUMAB, AND POST-RT BEVACIZUMAB AND TEMOZOLOMIDE: A PHASE II STUDY

Authors
Desjardins, A; Peters, KB; II, HJE; Bailey, LA; Alderson, LM; Ranjan, T; Sampson, JH; Friedman, AH; Bigner, DD; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, A, Peters, KB, II, HJE, Bailey, LA, Alderson, LM, Ranjan, T, Sampson, JH, Friedman, AH, Bigner, DD, Friedman, HS, and Vredenburgh, JJ. "NEWLY DIAGNOSED GLIOBLASTOMA TREATED WITH GLIADEL (R) FOLLOWED BY RADIATION THERAPY (RT), TEMOZOLOMIDE AND BEVACIZUMAB, AND POST-RT BEVACIZUMAB AND TEMOZOLOMIDE: A PHASE II STUDY." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
104
End Page
104

DEVELOPING RNA NANOPARTICLE VACCINES TARGETING PEDIATRIC AND ADULT BRAIN TUMORS

Authors
Sayour, EJ; Sanchez-Perez, L; Pham, C; Snyder, D; Xie, W; Cui, X; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Sayour, EJ, Sanchez-Perez, L, Pham, C, Snyder, D, Xie, W, Cui, X, Bigner, DD, Sampson, JH, and Mitchell, DA. "DEVELOPING RNA NANOPARTICLE VACCINES TARGETING PEDIATRIC AND ADULT BRAIN TUMORS." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
39
End Page
39

INTRAVENOUS TREATMENT WITH AN ENDOTHELIAL GROWTH FACTOR RECEPTOR VIII-TARGETED BISPECIFIC ANTIBODY SUCCESSFULLY TREATS WELL-ESTABLISHED BRAIN TUMORS

Authors
Choi, BD; Kuan, C-T; Cai, M; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Kuan, C-T, Cai, M, Bigner, DD, and Sampson, JH. "INTRAVENOUS TREATMENT WITH AN ENDOTHELIAL GROWTH FACTOR RECEPTOR VIII-TARGETED BISPECIFIC ANTIBODY SUCCESSFULLY TREATS WELL-ESTABLISHED BRAIN TUMORS." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
38
End Page
39

MYELOABLATIVE TEMOZOLOMIDE INCREASES ANTIGEN-SPECIFIC CD8(+) T-CELL VACCINE RESPONSES AND IS REQUIRED FOR EFFICACIOUS IMMUNOTHERAPY AGAINST INTRACEREBRAL TUMORS

Authors
Sanchez-Perez, L; Choi, B; Snyder, D; Cui, X; Schmittling, RJ; Flores, C; Johnson, L; Archer, GA; Bigner, DD; Mitchell, DA; Sampson, JH
MLA Citation
Sanchez-Perez, L, Choi, B, Snyder, D, Cui, X, Schmittling, RJ, Flores, C, Johnson, L, Archer, GA, Bigner, DD, Mitchell, DA, and Sampson, JH. "MYELOABLATIVE TEMOZOLOMIDE INCREASES ANTIGEN-SPECIFIC CD8(+) T-CELL VACCINE RESPONSES AND IS REQUIRED FOR EFFICACIOUS IMMUNOTHERAPY AGAINST INTRACEREBRAL TUMORS." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
40
End Page
40

DEVELOPMENT OF IMMUNOCOMPETENT SYNGENEIC MODELS OF MEDULLOBLASTOMA FOR EVALUATION OF IMMUNOTHERAPY

Authors
Pham, CD; Flores, C; Snyder, D; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Pham, CD, Flores, C, Snyder, D, Bigner, DD, Sampson, JH, and Mitchell, DA. "DEVELOPMENT OF IMMUNOCOMPETENT SYNGENEIC MODELS OF MEDULLOBLASTOMA FOR EVALUATION OF IMMUNOTHERAPY." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
163
End Page
163

ROLE OF HEMATOPOIETIC STEM CELLS IN ENHANCING THE ANTI-TUMOR EFFICACY OF ADOPTIVE CELLULAR THERAPY

Authors
Flores, CT; Snyder, D; Sanchez-Perez, L; Pham, C; Friedman, H; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Flores, CT, Snyder, D, Sanchez-Perez, L, Pham, C, Friedman, H, Bigner, DD, Sampson, JH, and Mitchell, DA. "ROLE OF HEMATOPOIETIC STEM CELLS IN ENHANCING THE ANTI-TUMOR EFFICACY OF ADOPTIVE CELLULAR THERAPY." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
35
End Page
35

NEUROKININ-1 RECEPTOR: A POTENTIAL TARGET TO INHIBIT PEDIATRIC GLIOBLASTOMAS

Authors
Brown, KE; Keir, ST; Sampson, JH; Bigner, DD; Kwatra, MM
MLA Citation
Brown, KE, Keir, ST, Sampson, JH, Bigner, DD, and Kwatra, MM. "NEUROKININ-1 RECEPTOR: A POTENTIAL TARGET TO INHIBIT PEDIATRIC GLIOBLASTOMAS." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
17
End Page
18

TARGETING CYTOMEGALOVIRUS ANTIGENS FOR GLIOBLASTOMA IMMUNOTHERAPY

Authors
Nair, S; Schmittling, R; Boczkowski, D; Archer, G; Bigner, DD; Sampson, JH; Mitchell, DA
MLA Citation
Nair, S, Schmittling, R, Boczkowski, D, Archer, G, Bigner, DD, Sampson, JH, and Mitchell, DA. "TARGETING CYTOMEGALOVIRUS ANTIGENS FOR GLIOBLASTOMA IMMUNOTHERAPY." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
32
End Page
32

ADOPTIVE CELLULAR THERAPY TARGETING RECURRENT MEDULLOBLASTOMA AND PRIMITIVE NEUROECTODERMAL TUMORS AFTER MYELOABLATIVE AND NON-MYELOABLATIVE CONDITIONING

Authors
Mitchell, DA; Gururangan, SG; Grant, G; Driscoll, T; Archer, G; King, J; Boczkowski, D; Xie, W; Nair, S; Perry, B; Fuchs, H; Kurtzberg, J; Friedman, H; Bigner, D; Sampson, J
MLA Citation
Mitchell, DA, Gururangan, SG, Grant, G, Driscoll, T, Archer, G, King, J, Boczkowski, D, Xie, W, Nair, S, Perry, B, Fuchs, H, Kurtzberg, J, Friedman, H, Bigner, D, and Sampson, J. "ADOPTIVE CELLULAR THERAPY TARGETING RECURRENT MEDULLOBLASTOMA AND PRIMITIVE NEUROECTODERMAL TUMORS AFTER MYELOABLATIVE AND NON-MYELOABLATIVE CONDITIONING." October 2012.
Source
wos-lite
Published In
Neuro-Oncology
Volume
14
Publish Date
2012
Start Page
49
End Page
49

Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Authors
Northcott, PA; Shih, DJH; Peacock, J; Garzia, L; Morrissy, AS; Zichner, T; Stütz, AM; Korshunov, A; Reimand, J; Schumacher, SE; Beroukhim, R; Ellison, DW; Marshall, CR; Lionel, AC; Mack, S; Dubuc, A; Yao, Y; Ramaswamy, V; Luu, B; Rolider, A; Cavalli, FMG; Wang, X; Remke, M; Wu, X; Chiu, RYB; Chu, A; Chuah, E; Corbett, RD; Hoad, GR; Jackman, SD; Li, Y; Lo, A; Mungall, KL; Nip, KM; Qian, JQ; Raymond, AGJ; Thiessen, NT; Varhol, RJ; Birol, I; Moore, RA; Mungall, AJ; Holt, R; Kawauchi, D et al.
MLA Citation
Northcott, PA, Shih, DJH, Peacock, J, Garzia, L, Morrissy, AS, Zichner, T, Stütz, AM, Korshunov, A, Reimand, J, Schumacher, SE, Beroukhim, R, Ellison, DW, Marshall, CR, Lionel, AC, Mack, S, Dubuc, A, Yao, Y, Ramaswamy, V, Luu, B, Rolider, A, Cavalli, FMG, Wang, X, Remke, M, Wu, X, Chiu, RYB, Chu, A, Chuah, E, Corbett, RD, Hoad, GR, Jackman, SD, Li, Y, Lo, A, Mungall, KL, Nip, KM, Qian, JQ, Raymond, AGJ, Thiessen, NT, Varhol, RJ, Birol, I, Moore, RA, Mungall, AJ, Holt, R, and Kawauchi, D et al. "Subgroup-specific structural variation across 1,000 medulloblastoma genomes." Nature 488.7409 (August 2, 2012): 49-56.
PMID
22832581
Source
pubmed
Published In
Nature
Volume
488
Issue
7409
Publish Date
2012
Start Page
49
End Page
56
DOI
10.1038/nature11327

Mutant IDH1 is required for IDH1 mutated tumor cell growth.

Frequent somatic hotspot mutations in isocitrate dehydrogenase 1 (IDH1) have been identified in gliomas, acute myeloid leukemias, chondrosarcomas, and other cancers, providing a likely avenue for targeted cancer therapy. However, whether mutant IDH1 protein is required for maintaining IDH1 mutated tumor cell growth remains unknown. Here, using a genetically engineered inducible system, we report that selective suppression of endogenous mutant IDH1 expression in HT1080, a fibrosarcoma cell line with a native IDH1(R132C) heterozygous mutation, significantly inhibits cell proliferation and decreases clonogenic potential. Our findings offer insights into changes that may contribute to the inhibition of cell proliferation and offer a strong preclinical rationale for utilizing mutant IDH1 as a valid therapeutic target.

Authors
Jin, G; Pirozzi, CJ; Chen, LH; Lopez, GY; Duncan, CG; Feng, J; Spasojevic, I; Bigner, DD; He, Y; Yan, H
MLA Citation
Jin, G, Pirozzi, CJ, Chen, LH, Lopez, GY, Duncan, CG, Feng, J, Spasojevic, I, Bigner, DD, He, Y, and Yan, H. "Mutant IDH1 is required for IDH1 mutated tumor cell growth." Oncotarget 3.8 (August 2012): 774-782.
PMID
22885298
Source
pubmed
Published In
Oncotarget
Volume
3
Issue
8
Publish Date
2012
Start Page
774
End Page
782
DOI
10.18632/oncotarget.577

Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas.

Mutations in the critical chromatin modifier ATRX and mutations in CIC and FUBP1, which are potent regulators of cell growth, have been discovered in specific subtypes of gliomas, the most common type of primary malignant brain tumors. However, the frequency of these mutations in many subtypes of gliomas, and their association with clinical features of the patients, is poorly understood. Here we analyzed these loci in 363 brain tumors. ATRX is frequently mutated in grade II-III astrocytomas (71%), oligoastrocytomas (68%), and secondary glioblastomas (57%), and ATRX mutations are associated with IDH1 mutations and with an alternative lengthening of telomeres phenotype. CIC and FUBP1 mutations occurred frequently in oligodendrogliomas (46% and 24%, respectively) but rarely in astrocytomas or oligoastrocytomas ( more than 10%). This analysis allowed us to define two highly recurrent genetic signatures in gliomas: IDH1/ATRX (I-A) and IDH1/CIC/FUBP1 (I-CF). Patients with I-CF gliomas had a significantly longer median overall survival (96 months) than patients with I-A gliomas (51 months) and patients with gliomas that did not harbor either signature (13 months). The genetic signatures distinguished clinically distinct groups of oligoastrocytoma patients, which usually present a diagnostic challenge, and were associated with differences in clinical outcome even among individual tumor types. In addition to providing new clues about the genetic alterations underlying gliomas, the results have immediate clinical implications, providing a tripartite genetic signature that can serve as a useful adjunct to conventional glioma classification that may aid in prognosis, treatment selection, and therapeutic trial design.

Authors
Jiao, Y; Killela, PJ; Reitman, ZJ; Rasheed, AB; Heaphy, CM; de Wilde, RF; Rodriguez, FJ; Rosemberg, S; Oba-Shinjo, SM; Nagahashi Marie, SK; Bettegowda, C; Agrawal, N; Lipp, E; Pirozzi, C; Lopez, G; He, Y; Friedman, H; Friedman, AH; Riggins, GJ; Holdhoff, M; Burger, P; McLendon, R; Bigner, DD; Vogelstein, B; Meeker, AK; Kinzler, KW; Papadopoulos, N; Diaz, LA; Yan, H
MLA Citation
Jiao, Y, Killela, PJ, Reitman, ZJ, Rasheed, AB, Heaphy, CM, de Wilde, RF, Rodriguez, FJ, Rosemberg, S, Oba-Shinjo, SM, Nagahashi Marie, SK, Bettegowda, C, Agrawal, N, Lipp, E, Pirozzi, C, Lopez, G, He, Y, Friedman, H, Friedman, AH, Riggins, GJ, Holdhoff, M, Burger, P, McLendon, R, Bigner, DD, Vogelstein, B, Meeker, AK, Kinzler, KW, Papadopoulos, N, Diaz, LA, and Yan, H. "Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas." Oncotarget 3.7 (July 2012): 709-722.
PMID
22869205
Source
pubmed
Published In
Oncotarget
Volume
3
Issue
7
Publish Date
2012
Start Page
709
End Page
722
DOI
10.18632/oncotarget.588

Internalization of the dual-specific immunotoxin D2C7-(scdsFv)-PE38KDEL in malignant glioma cell lines

Authors
Hedegaard, CJ; Pegram, CN; Bigner, DD; Poulsen, HS
MLA Citation
Hedegaard, CJ, Pegram, CN, Bigner, DD, and Poulsen, HS. "Internalization of the dual-specific immunotoxin D2C7-(scdsFv)-PE38KDEL in malignant glioma cell lines." April 15, 2012.
Source
wos-lite
Published In
Cancer Research
Volume
72
Publish Date
2012
DOI
10.1158/1538-7445.AM2012-2732

Abstract 1177: The mutational status of the p53 tumor suppressor gene is a determinant of GSTP1 expression and mediates GSTP1-dependent drug resistance in human glioblastoma

Authors
Antoun, GR; McLendon, R; Friedman, H; Friedman, A; Bigner, D; Ali-Osman, F
MLA Citation
Antoun, GR, McLendon, R, Friedman, H, Friedman, A, Bigner, D, and Ali-Osman, F. "Abstract 1177: The mutational status of the p53 tumor suppressor gene is a determinant of GSTP1 expression and mediates GSTP1-dependent drug resistance in human glioblastoma." April 15, 2012.
Source
crossref
Published In
Cancer Research
Volume
72
Issue
8 Supplement
Publish Date
2012
Start Page
1177
End Page
1177
DOI
10.1158/1538-7445.AM2012-1177

The medulloblastoma oncogene Otx2 enhances migration and permits ectopic proliferation of neuronal progenitor cells of the cerebellum and brainstem

Authors
Wortham, M; Jin, G; Sun, JL; Bigner, DD; Yan, H
MLA Citation
Wortham, M, Jin, G, Sun, JL, Bigner, DD, and Yan, H. "The medulloblastoma oncogene Otx2 enhances migration and permits ectopic proliferation of neuronal progenitor cells of the cerebellum and brainstem." April 15, 2012.
Source
wos-lite
Published In
Cancer Research
Volume
72
Publish Date
2012
DOI
10.1158/1538-7445.AM2012-3352

Deletion or epigenetic silencing of AJAP1 on 1p36 in glioblastoma.

Glioblastoma is universally fatal because of its propensity for rapid recurrence due to highly migratory tumor cells. Unraveling the genomic complexity that underlies this migratory characteristic could provide therapeutic targets that would greatly complement current surgical therapy. Using multiple high-resolution genomic screening methods, we identified a single locus, adherens junctional associated protein 1 (AJAP1) on chromosome 1p36 that is lost or epigenetically silenced in many glioblastomas. We found AJAP1 expression absent or reduced in 86% and 100% of primary glioblastoma tumors and cell lines, respectively, and the loss of expression correlates with AJAP1 methylation. Restoration of AJAP1 gene expression by transfection or demethylation agents results in decreased tumor cell migration in glioblastoma cell lines. This work shows the significant loss of expression of AJAP1 in glioblastoma and provides evidence of its role in the highly migratory characteristic of these tumors.

Authors
Lin, N; Di, C; Bortoff, K; Fu, J; Truszkowski, P; Killela, P; Duncan, C; McLendon, R; Bigner, D; Gregory, S; Adamson, DC
MLA Citation
Lin, N, Di, C, Bortoff, K, Fu, J, Truszkowski, P, Killela, P, Duncan, C, McLendon, R, Bigner, D, Gregory, S, and Adamson, DC. "Deletion or epigenetic silencing of AJAP1 on 1p36 in glioblastoma." Mol Cancer Res 10.2 (February 2012): 208-217.
PMID
22241217
Source
pubmed
Published In
Molecular cancer research : MCR
Volume
10
Issue
2
Publish Date
2012
Start Page
208
End Page
217
DOI
10.1158/1541-7786.MCR-10-0109

Radioimmunotargeting of malignant glioma by monoclonal antibody D2C7 reactive against both wild-type and variant III mutant epidermal growth factor receptors.

INTRODUCTION: Malignant glioma remains a significant therapeutic challenge, and immunotherapeutics might be a beneficial approach for these patients. A monoclonal antibody (MAb) specific for multiple molecular targets could expand the treatable patient population and the fraction of tumor cells targeted, with potentially increased efficacy. This motivated the generation of MAb D2C7, which recognizes both wild-type epidermal growth factor receptor (EGFRwt) and a tumor-specific mutant, EGFRvIII. METHODS: D2C7 binding affinity was determined by surface plasmon resonance and its specificity characterized through comparison to EGFRwt-specific EGFR.1 and EGFRvIII-specific L8A4 MAbs by flow cytometry and immunohistochemical analysis. The three MAbs were labeled with (125)I or (131)I using Iodogen, and paired-label internalization assays and biodistribution experiments in athymic mice with human tumor xenografts were performed. RESULTS: The affinity of D2C7 for EGFRwt and EGFRvIII was 5.2×10(9) M(-1) and 3.6×10(9) M(-1), and cell-surface reactivity with both receptors was documented by flow cytometry. Immunohistochemical analyses revealed D2C7 reactivity with malignant glioma tissue from 90 of 101 patients. Internalization assays performed on EGFRwt-expressing WTT cells and EGFRvIII-expressing NR6M cells indicated a threefold lower degradation of (125)I-labeled D2C7 compared with (131)I-labeled EGFR.1. Uptake of (125)I-labeled D2C7 in NR6M xenografts (52.45±13.97 %ID g(-1) on Day 3) was more than twice that of (131)I-labeled L8A4; a threefold to fivefold tumor delivery advantage was seen when compared to (131)I-labeled EGFR.1 in mice with WTT xenografts. CONCLUSIONS: These results suggest that D2C7 warrants further evaluation for the development of MAb-based therapeutics against cancers expressing EGFRwt and EGFRvIII.

Authors
Zalutsky, MR; Boskovitz, A; Kuan, C-T; Pegram, CN; Ayriss, J; Wikstrand, CJ; Buckley, AF; Lipp, ES; Herndon, JE; McLendon, RE; Bigner, DD
MLA Citation
Zalutsky, MR, Boskovitz, A, Kuan, C-T, Pegram, CN, Ayriss, J, Wikstrand, CJ, Buckley, AF, Lipp, ES, Herndon, JE, McLendon, RE, and Bigner, DD. "Radioimmunotargeting of malignant glioma by monoclonal antibody D2C7 reactive against both wild-type and variant III mutant epidermal growth factor receptors." Nucl Med Biol 39.1 (January 2012): 23-34.
PMID
21958852
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
39
Issue
1
Publish Date
2012
Start Page
23
End Page
34
DOI
10.1016/j.nucmedbio.2011.06.005

Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types.

Mutations in the chromatin remodeling gene ARID1A have recently been identified in the majority of ovarian clear cell carcinomas (OCCCs). To determine the prevalence of mutations in other tumor types, we evaluated 759 malignant neoplasms including those of the pancreas, breast, colon, stomach, lung, prostate, brain, and blood (leukemias). We identified truncating mutations in 6% of the neoplasms studied; nontruncating somatic mutations were identified in an additional 0.4% of neoplasms. Mutations were most commonly found in gastrointestinal samples with 12 of 119 (10%) colorectal and 10 of 100 (10%) gastric neoplasms, respectively, harboring changes. More than half of the mutated colorectal and gastric cancers displayed microsatellite instability (MSI) and the mutations in these tumors were out-of-frame insertions or deletions at mononucleotide repeats. Mutations were also identified in 2-8% of tumors of the pancreas, breast, brain (medulloblastomas), prostate, and lung, and none of these tumors displayed MSI. These findings suggest that the aberrant chromatin remodeling consequent to ARID1A inactivation contributes to a variety of different types of neoplasms.

Authors
Jones, S; Li, M; Parsons, DW; Zhang, X; Wesseling, J; Kristel, P; Schmidt, MK; Markowitz, S; Yan, H; Bigner, D; Hruban, RH; Eshleman, JR; Iacobuzio-Donahue, CA; Goggins, M; Maitra, A; Malek, SN; Powell, S; Vogelstein, B; Kinzler, KW; Velculescu, VE; Papadopoulos, N
MLA Citation
Jones, S, Li, M, Parsons, DW, Zhang, X, Wesseling, J, Kristel, P, Schmidt, MK, Markowitz, S, Yan, H, Bigner, D, Hruban, RH, Eshleman, JR, Iacobuzio-Donahue, CA, Goggins, M, Maitra, A, Malek, SN, Powell, S, Vogelstein, B, Kinzler, KW, Velculescu, VE, and Papadopoulos, N. "Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types." Hum Mutat 33.1 (January 2012): 100-103.
PMID
22009941
Source
pubmed
Published In
Human Mutation
Volume
33
Issue
1
Publish Date
2012
Start Page
100
End Page
103
DOI
10.1002/humu.21633

Toxin-based targeted therapy for malignant brain tumors.

Despite advances in conventional treatment modalities for malignant brain tumors-surgery, radiotherapy, and chemotherapy-the prognosis for patients with high-grade astrocytic tumor remains dismal. The highly heterogeneous and diffuse nature of astrocytic tumors calls for the development of novel therapies. Advances in genomic and proteomic research indicate that treatment of brain tumor patients can be increasingly personalized according to the characteristics of the targeted tumor and its environment. Consequently, during the last two decades, a novel class of investigative drug candidates for the treatment of central nervous system neoplasia has emerged: recombinant fusion protein conjugates armed with cytotoxic agents targeting tumor-specific antigens. The clinical applicability of the tumor-antigen-directed cytotoxic proteins as a safe and viable therapy for brain tumors is being investigated. Thus far, results from ongoing clinical trials are encouraging, as disease stabilization and patient survival prolongation have been observed in at least 109 cases. This paper summarizes the major findings pertaining to treatment with the different antiglioma cytotoxins at the preclinical and clinical stages.

Authors
Chandramohan, V; Sampson, JH; Pastan, I; Bigner, DD
MLA Citation
Chandramohan, V, Sampson, JH, Pastan, I, and Bigner, DD. "Toxin-based targeted therapy for malignant brain tumors." Clinical & developmental immunology 2012 (January 2012): 480429-. (Review)
PMID
22400035
Source
epmc
Published In
Clinical & Developmental Immunology (Hindawi)
Volume
2012
Publish Date
2012
Start Page
480429
DOI
10.1155/2012/480429

A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma.

BACKGROUND: Preclinical studies in mice have demonstrated that the prophylactic depletion of immunosuppressive regulatory T-cells (T(Regs)) through targeting the high affinity interleukin-2 (IL-2) receptor (IL-2Rα/CD25) can enhance anti-tumor immunotherapy. However, therapeutic approaches are complicated by the inadvertent inhibition of IL-2Rα expressing anti-tumor effector T-cells. OBJECTIVE: To determine if changes in the cytokine milieu during lymphopenia may engender differential signaling requirements that would enable unarmed anti-IL-2Rα monoclonal antibody (MAbs) to selectively deplete T(Regs) while permitting vaccine-stimulated immune responses. METHODOLOGY: A randomized placebo-controlled pilot study was undertaken to examine the ability of the anti-IL-2Rα MAb daclizumab, given at the time of epidermal growth factor receptor variant III (EGFRvIII) targeted peptide vaccination, to safely and selectively deplete T(Regs) in patients with glioblastoma (GBM) treated with lymphodepleting temozolomide (TMZ). RESULTS AND CONCLUSIONS: Daclizumab treatment (n = 3) was well-tolerated with no symptoms of autoimmune toxicity and resulted in a significant reduction in the frequency of circulating CD4+Foxp3+ TRegs in comparison to saline controls (n = 3)( p = 0.0464). A significant (p<0.0001) inverse correlation between the frequency of TRegs and the level of EGFRvIII specific humoral responses suggests the depletion of TRegs may be linked to increased vaccine-stimulated humoral immunity. These data suggest this approach deserves further study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00626015.

Authors
Sampson, JH; Schmittling, RJ; Archer, GE; Congdon, KL; Nair, SK; Reap, EA; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; Coan, A; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Mitchell, DA
MLA Citation
Sampson, JH, Schmittling, RJ, Archer, GE, Congdon, KL, Nair, SK, Reap, EA, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, Coan, A, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Mitchell, DA. "A pilot study of IL-2Rα blockade during lymphopenia depletes regulatory T-cells and correlates with enhanced immunity in patients with glioblastoma." PLoS One 7.2 (2012): e31046-.
PMID
22383993
Source
pubmed
Published In
PloS one
Volume
7
Issue
2
Publish Date
2012
Start Page
e31046
DOI
10.1371/journal.pone.0031046

Aberrant Otx2 expression enhances migration and induces ectopic proliferation of hindbrain neuronal progenitor cells.

Dysregulation of Otx2 is a hallmark of the pediatric brain tumor medulloblastoma, yet its functional significance in the establishment of these tumors is unknown. Here we have sought to determine the functional consequences of Otx2 overexpression in the mouse hindbrain to characterize its potential role in medulloblastoma tumorigenesis and identify the cell types responsive to this lineage-specific oncogene. Expression of Otx2 broadly in the mouse hindbrain resulted in the accumulation of proliferative clusters of cells in the cerebellar white matter and dorsal brainstem of postnatal mice. We found that brainstem ectopia were derived from neuronal progenitors of the rhombic lip and that cerebellar ectopia were derived from granule neuron precursors (GNPs) that had migrated inwards from the external granule layer (EGL). These hyperplasias exhibited various characteristics of medulloblastoma precursor cells identified in animal models of Shh or Wnt group tumors, including aberrant localization and altered spatiotemporal control of proliferation. However, ectopia induced by Otx2 differentiated and dispersed as the animals reached adulthood, indicating that factors restricting proliferative lifespan were a limiting factor to full transformation of these cells. These studies implicate a role for Otx2 in altering the dynamics of neuronal progenitor cell proliferation.

Authors
Wortham, M; Jin, G; Sun, JL; Bigner, DD; He, Y; Yan, H
MLA Citation
Wortham, M, Jin, G, Sun, JL, Bigner, DD, He, Y, and Yan, H. "Aberrant Otx2 expression enhances migration and induces ectopic proliferation of hindbrain neuronal progenitor cells." PLoS One 7.4 (2012): e36211-.
PMID
22558385
Source
pubmed
Published In
PloS one
Volume
7
Issue
4
Publish Date
2012
Start Page
e36211
DOI
10.1371/journal.pone.0036211

Immunotherapy of brain tumors.

Authors
Marshall, D; Mitchell, DA; Graner, MW; Bigner, DD
MLA Citation
Marshall, D, Mitchell, DA, Graner, MW, and Bigner, DD. "Immunotherapy of brain tumors." Handb Clin Neurol 104 (2012): 309-330. (Review)
PMID
22230450
Source
pubmed
Published In
Handbook of clinical neurology / edited by P.J. Vinken and G.W. Bruyn
Volume
104
Publish Date
2012
Start Page
309
End Page
330
DOI
10.1016/B978-0-444-52138-5.00020-7

Central nervous system

Several different types of tumors, benign and malignant, have been identified in the central nervous system (CNS). The prognoses for these tumors are related to several factors, such as the age of the patient and the location and histology of the tumor. In adults, about half of all CNS tumors are malignant, whereas in pediatric patients, more than 75% are malignant. For most benign CNS tumors that require treatment, neurosurgeons can offer curative resections or at least provide significant relief from mass effect. Unfortunately, we still lack effective treatments for most primary and secondary malignant CNS tumors. However, the past decade has witnessed an explosion in the understanding of the early molecular events in malignant primary CNS tumors, and for the first time in history, oncologists are seeing that a plethora of new therapies targeting these molecular events are being tested in clinical trials. There is hope on the horizon for the fight against these deadly tumors. The distribution of CNS tumors by location has remained constant for numerous years. The majority of primary CNS tumors arise in the major cortical lobes. Twenty nine percent of primary CNS tumors arise from the dural meninges that encase the CNS structures. The vast majority of these are meningiomas, of which over 90% are benign. About 10% of primary CNS tumors are found in the sella turcica region, where the pituitary gland resides. Other much less common sites of primary CNS tumors include the pineal region, ventricular system, cerebellum, brain stem, cranial nerves, and spinal cord. The distribution of CNS tumors by histology has seen a slight increase in more malignant tumors over the past decade, possibly due to increased neuroimaging practices or environmental exposures. Arising from glial cells, gliomas represent over 36% of all primary CNS tumors and consist of astrocytomas, oligodendrogliomas, ependymomas, mixed gliomas, and neuroepithelial tumors. The benign meningiomas make up 32% of primary CNS tumors, followed by nerve sheath tumors and pituitary tumors. Primary CNS lymphomas, embryonal tumors, and craniopharyngiomas are uncommon. The most common gliomas are astrocytomas, and these tumors are typically classified by the World Health Organization (WHO) as Grades I through IV. Grade IV, the most malignant grade of astrocytoma, includes glioblastoma multiforme (GBM), the most common malignant primary CNS glioma in adults, which represents 51% of all primary CNS gliomas. GBM is unfortunately the most challenging to effectively treat and has the worst patient survival. This chapter is therefore primarily devoted to the current understanding of this topic. Here we describe the molecular and cellular events associated with malignant glioma initiation and progression. We also review the importance of glioma stem cell biology and tumor immunology in early gliomagenesis. In addition, we present a brief description of the most common malignant primary CNS glioma in pediatric patients - medulloblastoma, as well as familial cancer syndromes that include gliomas as part of the syndrome. © 2012 IOS Press and the authors. All rights reserved.

Authors
Adamsona, DC; Rasheed, BAK; McLendon, RE; Bigner, DD
MLA Citation
Adamsona, DC, Rasheed, BAK, McLendon, RE, and Bigner, DD. "Central nervous system." Translational Pathology of Early Cancer (2012): 193-210.
Source
scival
Published In
Translational Pathology of Early Cancer
Publish Date
2012
Start Page
193
End Page
210
DOI
10.3233/978-1-61499-024-6-193

Central nervous system

Several different types of tumors, benign and malignant, have been identified in the central nervous system (CNS). The prognoses for these tumors are related to several factors, such as the age of the patient and the location and histology of the tumor. In adults, about half of all CNS tumors are malignant, whereas in pediatric patients, more than 75% are malignant. For most benign CNS tumors that require treatment, neurosurgeons can offer curative resections or at least provide significant relief from mass effect. Unfortunately, we still lack effective treatments for most primary and secondary malignant CNS tumors. However, the past decade has witnessed an explosion in the understanding of the early molecular events in malignant primary CNS tumors, and for the first time in history, oncologists are seeing that a plethora of new therapies targeting these molecular events are being tested in clinical trials. There is hope on the horizon for the fight against these deadly tumors. The distribution of CNS tumors by location has remained constant for numerous years. The majority of primary CNS tumors arise in the major cortical lobes. Twenty nine percent of primary CNS tumors arise from the dural meninges that encase the CNS structures. The vast majority of these are meningiomas, of which over 90% are benign. About 10% of primary CNS tumors are found in the sella turcica region, where the pituitary gland resides. Other much less common sites of primary CNS tumors include the pineal region, ventricular system, cerebellum, brain stem, cranial nerves, and spinal cord. The distribution of CNS tumors by histology has seen a slight increase in more malignant tumors over the past decade, possibly due to increased neuroimaging practices or environmental exposures. Arising from glial cells, gliomas represent over 36% of all primary CNS tumors and consist of astrocytomas, oligodendrogliomas, ependymomas, mixed gliomas, and neuroepithelial tumors. The benign meningiomas make up 32% of primary CNS tumors, followed by nerve sheath tumors and pituitary tumors. Primary CNS lymphomas, embryonal tumors, and craniopharyngiomas are uncommon. The most common gliomas are astrocytomas, and these tumors are typically classified by the World Health Organization (WHO) as Grades I through IV. Grade IV, the most malignant grade of astrocytoma, includes glioblastoma multiforme (GBM), the most common malignant primary CNS glioma in adults, which represents 51% of all primary CNS gliomas. GBM is unfortunately the most challenging to effectively treat and has the worst patient survival. This chapter is therefore primarily devoted to the current understanding of this topic. Here we describe the molecular and cellular events associated with malignant glioma initiation and progression. We also review the importance of glioma stem cell biology and tumor immunology in early gliomagenesis. In addition, we present a brief description of the most common malignant primary CNS glioma in pediatric patients - medulloblastoma, as well as familial cancer syndromes that include gliomas as part of the syndrome. © 2012 IOS Press and the authors. All rights reserved.

Authors
Adamsona, DC; Rasheed, BAK; McLendon, RE; Bigner, DD
MLA Citation
Adamsona, DC, Rasheed, BAK, McLendon, RE, and Bigner, DD. "Central nervous system." Translational Pathology of Early Cancer (2012): 193-210.
Source
scival
Published In
Translational Pathology of Early Cancer
Publish Date
2012
Start Page
193
End Page
210
DOI
10.3233/978-1-61499-024-6-193

DENDRITIC CELL VACCINES TARGETING CYTOMEGALOVIRUS IN GLIOBLASTOMA

Authors
Mitchell, DA; Archer, GE; Friedman, HS; Herndon, JE; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Archer, GE, Friedman, HS, Herndon, JE, Bigner, DD, and Sampson, JH. "DENDRITIC CELL VACCINES TARGETING CYTOMEGALOVIRUS IN GLIOBLASTOMA." NEURO-ONCOLOGY 13 (November 2011): 39-39.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
39
End Page
39

TRUNCATED NEUROKININ 1 RECEPTOR: EXPRESSION IN PRIMARY GLIOBLASTOMAS AND RELATIONSHIP WITH PATIENT SURVIVAL

Authors
Kwatra, MM; Porter, TM; Brown, KE; Herndon, JE; Bigner, DD
MLA Citation
Kwatra, MM, Porter, TM, Brown, KE, Herndon, JE, and Bigner, DD. "TRUNCATED NEUROKININ 1 RECEPTOR: EXPRESSION IN PRIMARY GLIOBLASTOMAS AND RELATIONSHIP WITH PATIENT SURVIVAL." NEURO-ONCOLOGY 13 (November 2011): 82-82.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
82
End Page
82

MIBEFRADIL, A NOVEL THERAPY FOR GLIOBLATOMA MULTIFORME: INTERLACED THERAPY IN A MURINE MODEL

Authors
Keir, ST; Reardon, DA; Saling, JR; Gray, LS; Bigner, DD; Friedman, HS
MLA Citation
Keir, ST, Reardon, DA, Saling, JR, Gray, LS, Bigner, DD, and Friedman, HS. "MIBEFRADIL, A NOVEL THERAPY FOR GLIOBLATOMA MULTIFORME: INTERLACED THERAPY IN A MURINE MODEL." NEURO-ONCOLOGY 13 (November 2011): 108-109.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
108
End Page
109

ACTIVITY OF THE PAN-HER INHIBITOR PF-00299804 AGAINST A PANEL OF BRAIN TUMOR XENOGRAFTS

Authors
Keir, ST; Reardon, DA; Friedman, HS; Bigner, DD
MLA Citation
Keir, ST, Reardon, DA, Friedman, HS, and Bigner, DD. "ACTIVITY OF THE PAN-HER INHIBITOR PF-00299804 AGAINST A PANEL OF BRAIN TUMOR XENOGRAFTS." NEURO-ONCOLOGY 13 (November 2011): 164-164.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
164
End Page
164

PRECLINICAL USE OF MILD HYPERTHERMIA TO ENHANCE DRUG DELIVERY TO BRAIN TUMORS

Authors
Grant, GA; Wilson, C; Salami, S; Macaroni, P; Li, S; Park, J-Y; Needham, D; Bigner, D; Dewhirst, M
MLA Citation
Grant, GA, Wilson, C, Salami, S, Macaroni, P, Li, S, Park, J-Y, Needham, D, Bigner, D, and Dewhirst, M. "PRECLINICAL USE OF MILD HYPERTHERMIA TO ENHANCE DRUG DELIVERY TO BRAIN TUMORS." NEURO-ONCOLOGY 13 (November 2011): 111-111.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
111
End Page
111

Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans.

Lymphodepletion augments adoptive cell transfer during antitumor immunotherapy, producing dramatic clinical responses in patients with malignant melanoma. We report that the lymphopenia induced by the chemotherapeutic agent temozolomide (TMZ) enhances vaccine-driven immune responses and significantly reduces malignant growth in an established model of murine tumorigenesis. Unexpectedly, despite the improved antitumor efficacy engendered by TMZ-induced lymphopenia, there was a treatment related increase in the frequency of immunosuppressive regulatory T cells (T(Regs); P = .0006). Monoclonal antibody (mAb)-mediated inhibition of the high-affinity IL-2 receptor α (IL-2Rα/CD25) during immunotherapy in normal mice depleted T(Regs) (73% reduction; P = .0154) but also abolished vaccine-induced immune responses. However, during lymphodepletion, IL-2Rα blockade decreased T(Regs) (93% reduction; P = .0001) without impairing effector T-cell responses, to augment therapeutic antitumor efficacy (66% reduction in tumor growth; P = .0024). Of clinical relevance, we also demonstrate that anti-IL-2Rα mAb administration during recovery from lymphodepletive TMZ in patients with glioblastoma reduced T(Reg) frequency (48% reduction; P = .0061) while permitting vaccine-stimulated antitumor effector cell expansion. To our knowledge, this is the first report of systemic antibody-mediated T(Reg) depletion during lymphopenia and the consequent synergistic enhancement of vaccine-driven cellular responses, as well as the first demonstration that anti-IL-2Rα mAbs function differentially in nonlymphopenic versus lymphopenic contexts.

Authors
Mitchell, DA; Cui, X; Schmittling, RJ; Sanchez-Perez, L; Snyder, DJ; Congdon, KL; Archer, GE; Desjardins, A; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Reardon, DA; Vredenburgh, JJ; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Cui, X, Schmittling, RJ, Sanchez-Perez, L, Snyder, DJ, Congdon, KL, Archer, GE, Desjardins, A, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Reardon, DA, Vredenburgh, JJ, Bigner, DD, and Sampson, JH. "Monoclonal antibody blockade of IL-2 receptor α during lymphopenia selectively depletes regulatory T cells in mice and humans." Blood 118.11 (September 15, 2011): 3003-3012.
PMID
21768296
Source
pubmed
Published In
Blood
Volume
118
Issue
11
Publish Date
2011
Start Page
3003
End Page
3012
DOI
10.1182/blood-2011-02-334565

Mutations in CIC and FUBP1 contribute to human oligodendroglioma.

Oligodendrogliomas are the second most common malignant brain tumor in adults and exhibit characteristic losses of chromosomes 1p and 19q. To identify the molecular genetic basis for this alteration, we performed exomic sequencing of seven tumors. Among other changes, we found that the CIC gene (homolog of the Drosophila gene capicua) on chromosome 19q was somatically mutated in six cases and that the FUBP1 gene [encoding far-upstream element (FUSE) binding protein] on chromosome 1p was somatically mutated in two tumors. Examination of 27 additional oligodendrogliomas revealed 12 and 3 more tumors with mutations of CIC and FUBP1, respectively, 58% of which were predicted to result in truncations of the encoded proteins. These results suggest a critical role for these genes in the biology and pathology of oligodendrocytes.

Authors
Bettegowda, C; Agrawal, N; Jiao, Y; Sausen, M; Wood, LD; Hruban, RH; Rodriguez, FJ; Cahill, DP; McLendon, R; Riggins, G; Velculescu, VE; Oba-Shinjo, SM; Marie, SKN; Vogelstein, B; Bigner, D; Yan, H; Papadopoulos, N; Kinzler, KW
MLA Citation
Bettegowda, C, Agrawal, N, Jiao, Y, Sausen, M, Wood, LD, Hruban, RH, Rodriguez, FJ, Cahill, DP, McLendon, R, Riggins, G, Velculescu, VE, Oba-Shinjo, SM, Marie, SKN, Vogelstein, B, Bigner, D, Yan, H, Papadopoulos, N, and Kinzler, KW. "Mutations in CIC and FUBP1 contribute to human oligodendroglioma." Science 333.6048 (September 9, 2011): 1453-1455.
PMID
21817013
Source
pubmed
Published In
Science
Volume
333
Issue
6048
Publish Date
2011
Start Page
1453
End Page
1455
DOI
10.1126/science.1210557

Convection-enhanced delivery.

Authors
Sampson, JH; Raghavan, R; Brady, M; Friedman, AH; Bigner, D
MLA Citation
Sampson, JH, Raghavan, R, Brady, M, Friedman, AH, and Bigner, D. "Convection-enhanced delivery." J Neurosurg 115.3 (September 2011): 463-464.
PMID
21619413
Source
pubmed
Published In
Journal of neurosurgery
Volume
115
Issue
3
Publish Date
2011
Start Page
463
End Page
464
DOI
10.3171/2010.11.JNS101801

Colocalization of gadolinium-diethylene triamine pentaacetic acid with high-molecular-weight molecules after intracerebral convection-enhanced delivery in humans.

BACKGROUND: Convection-enhanced delivery (CED) permits site-specific therapeutic drug delivery within interstitial spaces at increased dosages through circumvention of the blood-brain barrier. CED is currently limited by suboptimal methodologies for monitoring the delivery of therapeutic agents that would permit technical optimization and enhanced therapeutic efficacy. OBJECTIVE: To determine whether a readily available small-molecule MRI contrast agent, gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA), could effectively track the distribution of larger therapeutic agents. METHODS: Gd-DTPA was coinfused with the larger molecular tracer, I-labeled human serum albumin (I-HSA), during CED of an EGFRvIII-specific immunotoxin as part of treatment for a patient with glioblastoma. RESULTS: Infusion of both tracers was safe in this patient. Analysis of both Gd-DTPA and I-HSA during and after infusion revealed a high degree of anatomical and volumetric overlap. CONCLUSION: Gd-DTPA may be able to accurately demonstrate the anatomic and volumetric distribution of large molecules used for antitumor therapy with high resolution and in combination with fluid-attenuated inversion recovery (FLAIR) imaging, and provide additional information about leaks into cerebrospinal fluid spaces and resection cavities. Similar studies should be performed in additional patients to validate our findings and help refine the methodologies we used.

Authors
Sampson, JH; Brady, M; Raghavan, R; Mehta, AI; Friedman, AH; Reardon, DA; Petry, NA; Barboriak, DP; Wong, TZ; Zalutsky, MR; Lally-Goss, D; Bigner, DD
MLA Citation
Sampson, JH, Brady, M, Raghavan, R, Mehta, AI, Friedman, AH, Reardon, DA, Petry, NA, Barboriak, DP, Wong, TZ, Zalutsky, MR, Lally-Goss, D, and Bigner, DD. "Colocalization of gadolinium-diethylene triamine pentaacetic acid with high-molecular-weight molecules after intracerebral convection-enhanced delivery in humans." Neurosurgery 69.3 (September 2011): 668-676.
PMID
21430586
Source
pubmed
Published In
Neurosurgery
Volume
69
Issue
3
Publish Date
2011
Start Page
668
End Page
676
DOI
10.1227/NEU.0b013e3182181ba8

Altered telomeres in tumors with ATRX and DAXX mutations.

The proteins encoded by ATRX and DAXX participate in chromatin remodeling at telomeres and other genomic sites. Because inactivating mutations of these genes are common in human pancreatic neuroendocrine tumors (PanNETs), we examined the telomere status of these tumors. We found that 61% of PanNETs displayed abnormal telomeres that are characteristic of a telomerase-independent telomere maintenance mechanism termed ALT (alternative lengthening of telomeres). All of the PanNETs exhibiting these abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein. ATRX mutations also correlate with abnormal telomeres in tumors of the central nervous system. These data suggest that an alternative telomere maintenance function may operate in human tumors with alterations in the ATRX or DAXX genes.

Authors
Heaphy, CM; de Wilde, RF; Jiao, Y; Klein, AP; Edil, BH; Shi, C; Bettegowda, C; Rodriguez, FJ; Eberhart, CG; Hebbar, S; Offerhaus, GJ; McLendon, R; Rasheed, BA; He, Y; Yan, H; Bigner, DD; Oba-Shinjo, SM; Marie, SKN; Riggins, GJ; Kinzler, KW; Vogelstein, B; Hruban, RH; Maitra, A; Papadopoulos, N; Meeker, AK
MLA Citation
Heaphy, CM, de Wilde, RF, Jiao, Y, Klein, AP, Edil, BH, Shi, C, Bettegowda, C, Rodriguez, FJ, Eberhart, CG, Hebbar, S, Offerhaus, GJ, McLendon, R, Rasheed, BA, He, Y, Yan, H, Bigner, DD, Oba-Shinjo, SM, Marie, SKN, Riggins, GJ, Kinzler, KW, Vogelstein, B, Hruban, RH, Maitra, A, Papadopoulos, N, and Meeker, AK. "Altered telomeres in tumors with ATRX and DAXX mutations." Science 333.6041 (July 22, 2011): 425-.
PMID
21719641
Source
pubmed
Published In
Science
Volume
333
Issue
6041
Publish Date
2011
Start Page
425
DOI
10.1126/science.1207313

Affinity-matured anti-glycoprotein NMB recombinant immunotoxins targeting malignant gliomas and melanomas.

Glycoprotein NMB (GPNMB), a transmembrane glycoprotein highly expressed in high-grade gliomas (HGGs), is an attractive target in cancer immunotherapy. We isolated a GPNMB-specific scFv clone, G49, from a human synthetic phage-display library. To obtain mutant single-chain variable-fragment antibodies (scFvs) with improved affinity and immunotoxins with increased activity, we subjected G49 to in vitro affinity maturation by a complementarity-determining-region (CDR) random-mutagenesis technique. Using light-chain CDR3 mutagenesis, cell-based panning by phage display, subsequent heavy-chain CDR1 mutagenesis, and flow-cytometric selection by yeast-surface display, we generated the mutant scFv clone 902V, with an overall 11-fold increase in affinity for GPNMB. Clone 902V was further randomized throughout the whole scFv by error-prone PCR, and one mutant, F6V, was selected by yeast-surface display. F6V scFv, differing from 902V by one amino-acid change in the light-chain CDR2, exhibited an affinity for GPNMB of 0.30 nM. The F6V mutant scFv clone was fused with a truncated form of Pseudomonas exotoxin A to form the immunotoxin F6V-PE38. F6V-PE38 demonstrated significant protein-synthesis-inhibition activity on GPNMB-expressing glioma and malignant melanoma cells (IC(50) = 0.5 ng/ml [8 pM]), a 60-fold improvement over G49 activity, but no cytotoxicity on GPNMB-negative cells. Furthermore, F6V-PE38 exhibited significant antitumor activity against subcutaneous malignant glioma xenografts in two nude-mouse models and a melanoma neoplastic meningitis model in athymic rats. These GPNMB-specific scFv antibodies and immunotoxins hold promise as reagents in targeted therapy for HGGs and other GPNMB-expressing malignancies.

Authors
Kuan, C-T; Wakiya, K; Keir, ST; Li, J; Herndon, JE; Pastan, I; Bigner, DD
MLA Citation
Kuan, C-T, Wakiya, K, Keir, ST, Li, J, Herndon, JE, Pastan, I, and Bigner, DD. "Affinity-matured anti-glycoprotein NMB recombinant immunotoxins targeting malignant gliomas and melanomas." Int J Cancer 129.1 (July 1, 2011): 111-121.
PMID
20824708
Source
pubmed
Published In
International Journal of Cancer
Volume
129
Issue
1
Publish Date
2011
Start Page
111
End Page
121
DOI
10.1002/ijc.25645

Bispecific antibodies engage T cells for antitumor immunotherapy.

INTRODUCTION: Although considerable evidence supports the hypothesis that T cells play a critical role in the immune response against cancer, the ability to mount and sustain tumor-specific cellular responses in vivo remains a challenge. A strategy that harnesses the cytotoxic advantage of T cell therapy is the use of bispecific antibodies designed to engage and activate endogenous polyclonal T cell populations via the CD3 complex, but only in the presence of a tumor antigen. While antibody constructs with dual specificity were first described as anticancer therapeutics over 25 years ago, it was not until recently that one subclass of bispecific single-chain antibody, the bispecific T cell engager (BiTE), emerged as superior to previous iterations in achieving efficacy in animal models and early clinical trials. AREAS COVERED: The evolution of bispecific antibodies in antitumor immunotherapy is reviewed and the greatest hurdles impeding their clinical translation are discussed, specifically in the context of immunoprivileged sites as is the case for intracerebral malignancy. EXPERT OPINION: The BiTE platform has great potential in the treatment of malignant disease. Despite burgeoning interest in bispecific antibodies and permutations thereof, the issues of stability and cost-effective production persist as obstacles.

Authors
Choi, BD; Cai, M; Bigner, DD; Mehta, AI; Kuan, C-T; Sampson, JH
MLA Citation
Choi, BD, Cai, M, Bigner, DD, Mehta, AI, Kuan, C-T, and Sampson, JH. "Bispecific antibodies engage T cells for antitumor immunotherapy." Expert Opin Biol Ther 11.7 (July 2011): 843-853. (Review)
PMID
21449821
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
11
Issue
7
Publish Date
2011
Start Page
843
End Page
853
DOI
10.1517/14712598.2011.572874

The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma.

PURPOSE: To determine if the addition of bevacizumab to radiation therapy and temozolomide, followed by bevacizumab, temozolomide, and irinotecan, for newly diagnosed glioblastoma patients is safe and effective. EXPERIMENTAL DESIGN: A total of 75 patients with newly diagnosed glioblastoma were enrolled in the phase II trial that investigated the addition of bevacizumab to standard radiation therapy and daily temozolomide followed by the addition of bevacizumab and irinotecan to adjuvant temozolomide. The bevacizumab was given at 10 mg/kg every 14 days beginning a minimum of 4 weeks postcraniotomy. Two weeks after radiation therapy, the patients began 6 to 12 cycles of 5-day temozolomide with bevacizumab and irinotecan every 14 days. The primary endpoint was the proportion of patients alive 16 months after informed consent. RESULTS: The therapy had moderate toxicity. Three patients, one of whom had a grade 2 central nervous system hemorrhage, came off study during radiation therapy. Seventy patients started the postradiation therapy, and 16 (23%) terminated this adjuvant therapy early because of toxicity. The median overall survival was 21.2 months (95% CI: 17.2-25.4), and 65% of the patients were alive at 16 months (95% CI: 53.4-74.9). The median progression-free survival was 14.2 months (95% CI: 12-16). CONCLUSION: The addition of bevacizumab to standard radiation therapy and temozolomide, followed by bevacizumab, irinotecan, and temozolomide, for the treatment of newly diagnosed glioblastoma has moderate toxicity and may improve efficacy compared with historical controls. The results from phase III trials are required before the role of bevacizumab for newly diagnosed glioblastoma is established.

Authors
Vredenburgh, JJ; Desjardins, A; Reardon, DA; Peters, KB; Herndon, JE; Marcello, J; Kirkpatrick, JP; Sampson, JH; Bailey, L; Threatt, S; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Vredenburgh, JJ, Desjardins, A, Reardon, DA, Peters, KB, Herndon, JE, Marcello, J, Kirkpatrick, JP, Sampson, JH, Bailey, L, Threatt, S, Friedman, AH, Bigner, DD, and Friedman, HS. "The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma." Clin Cancer Res 17.12 (June 15, 2011): 4119-4124.
PMID
21531816
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
17
Issue
12
Publish Date
2011
Start Page
4119
End Page
4124
DOI
10.1158/1078-0432.CCR-11-0120

Medical diagnostic radiation exposures and risk of gliomas.

High-dose ionizing radiation is an established risk factor for glioma, but it remains unknown whether moderate- and low-dose radiation increase glioma risk. In this analysis, we assessed the evidence that self-reported exposures to diagnostic ionizing radiation, including computerized tomography (CT) scans, is associated with increased risk of adult glioma. While no independent association was observed for CT scans alone (3+ scans compared to none P = 0.08 and 1-2 scans compared to none P = 0.68), our findings suggest an increased risk of adult gliomas with cumulative exposure to three or more CT scans to the head and neck region (OR = 1.97, 95% CI: 0.92-4.23) limited to those who reported a family history of cancer: the P value for the interaction between having three or more CT scans and family history of cancer was 0.08. The stratum-specific adjusted OR for those with family history of cancer was more than three times that for the sub-group without family history of cancer. While there is some potential for symptom-related bias, one might expect this to be present for all diagnostic procedures rather than specific to one procedure. The interaction between CT scans and glioma with family history of cancer supports the biological plausibility of our findings, because similar results have been found for breast cancer and radiation. This observational data will increase awareness about potential risks associated with CT scans and the need to minimize the use of unnecessary examinations.

Authors
Davis, F; Il'yasova, D; Rankin, K; McCarthy, B; Bigner, DD
MLA Citation
Davis, F, Il'yasova, D, Rankin, K, McCarthy, B, and Bigner, DD. "Medical diagnostic radiation exposures and risk of gliomas." Radiat Res 175.6 (June 2011): 790-796.
PMID
21466382
Source
pubmed
Published In
Radiation Research
Volume
175
Issue
6
Publish Date
2011
Start Page
790
End Page
796
DOI
10.1667/RR2186.1

METABOLOMIC PROFILING OF A GLIOMA CELL LINE EXPRESSING IDH1 AND IDH2 MUTANTS

Authors
Reitman, ZJ; Jin, G; Karoly, ED; Spasojevic, I; Yang, J; Kinzler, KW; He, Y; Bigner, DD; Vogelstein, B; Yan, H
MLA Citation
Reitman, ZJ, Jin, G, Karoly, ED, Spasojevic, I, Yang, J, Kinzler, KW, He, Y, Bigner, DD, Vogelstein, B, and Yan, H. "METABOLOMIC PROFILING OF A GLIOMA CELL LINE EXPRESSING IDH1 AND IDH2 MUTANTS." May 2011.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I22
End Page
I23

TARGETED RADIOTHERAPY OF MEDULLOBLASTOMA USING SOMATOSTATIN RECEPTOR AVID RADIOLABELED PEPTIDES

Authors
Vaidyanathan, G; Li, J; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Li, J, Bigner, DD, and Zalutsky, MR. "TARGETED RADIOTHERAPY OF MEDULLOBLASTOMA USING SOMATOSTATIN RECEPTOR AVID RADIOLABELED PEPTIDES." May 2011.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I27
End Page
I27

CLINICAL PATHOLOGIC DESCRIPTION OF THREE PEDIATRIC MEDULLOBLASTOMA CASES WITH MLL2/3 GENE MUTATIONS

Authors
He, Y; Lopez, G; Grant, G; Fuchs, H; Leithe, L; Gururangan, S; Bigner, D; Yan, H; Mclendon, R
MLA Citation
He, Y, Lopez, G, Grant, G, Fuchs, H, Leithe, L, Gururangan, S, Bigner, D, Yan, H, and Mclendon, R. "CLINICAL PATHOLOGIC DESCRIPTION OF THREE PEDIATRIC MEDULLOBLASTOMA CASES WITH MLL2/3 GENE MUTATIONS." May 2011.
PMID
23659599
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I30
End Page
I30

GAIN-OF-FUNCTION tGLI1 TRANSCRIPTION FACTOR AUGMENTS ANCHORAGE-INDEPENDENT GROWTH OF MEDULLOBLASTOMA CELLS AND CONFERS THEIR RESISTANCE TO SMO INHIBITORS

Authors
Cao, X; Zhu, H; Bigner, D; Ali-Osman, F; Lo, H-W
MLA Citation
Cao, X, Zhu, H, Bigner, D, Ali-Osman, F, and Lo, H-W. "GAIN-OF-FUNCTION tGLI1 TRANSCRIPTION FACTOR AUGMENTS ANCHORAGE-INDEPENDENT GROWTH OF MEDULLOBLASTOMA CELLS AND CONFERS THEIR RESISTANCE TO SMO INHIBITORS." May 2011.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I9
End Page
I9

UPREGULATION OF VEGF-A GENE EXPRESSION BY THE tGLI1 TRANSCRIPTION FACTOR CONTRIBUTES TO GLIOBLASTOMA ANGIOGENESIS

Authors
Zhu, H; Cao, X; Keir, S; Bigner, D; Ali-Osman, F; Lo, H-W
MLA Citation
Zhu, H, Cao, X, Keir, S, Bigner, D, Ali-Osman, F, and Lo, H-W. "UPREGULATION OF VEGF-A GENE EXPRESSION BY THE tGLI1 TRANSCRIPTION FACTOR CONTRIBUTES TO GLIOBLASTOMA ANGIOGENESIS." May 2011.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I15
End Page
I16

EGFR AND EGFRvIII UNDERGO STRESS- AND EGFR KINASE INHIBITOR-INDUCED MITOCHONDRIAL TRANSLOCALIZATION IN GLIOBLASTOMA: A POTENTIAL MECHANISM OF EGFR- AND EGFRvIII-DRIVEN ANTAGONISM OF APOPTOSIS AND DRUG RESPONSE

Authors
Cao, X; Zhu, H; Bigner, D; Ali-Osman, F; Lo, H-W
MLA Citation
Cao, X, Zhu, H, Bigner, D, Ali-Osman, F, and Lo, H-W. "EGFR AND EGFRvIII UNDERGO STRESS- AND EGFR KINASE INHIBITOR-INDUCED MITOCHONDRIAL TRANSLOCALIZATION IN GLIOBLASTOMA: A POTENTIAL MECHANISM OF EGFR- AND EGFRvIII-DRIVEN ANTAGONISM OF APOPTOSIS AND DRUG RESPONSE." May 2011.
Source
wos-lite
Published In
Neuro-Oncology
Volume
13
Publish Date
2011
Start Page
I8
End Page
I9

Abstract LB-257: Profiling the effects of IDH1 and IDH2 mutants on the glioma cell metabolome

Authors
Yan, H; Reitman, ZJ; Jin, G; Spasojevic, I; He, Y; Bigner, DD; Karoly, ED; Yang, J; Kinzler, KW; Vogelstein, B
MLA Citation
Yan, H, Reitman, ZJ, Jin, G, Spasojevic, I, He, Y, Bigner, DD, Karoly, ED, Yang, J, Kinzler, KW, and Vogelstein, B. "Abstract LB-257: Profiling the effects of IDH1 and IDH2 mutants on the glioma cell metabolome." April 15, 2011.
Source
crossref
Published In
Cancer Research
Volume
71
Issue
8 Supplement
Publish Date
2011
Start Page
LB-257
End Page
LB-257
DOI
10.1158/1538-7445.AM2011-LB-257

Abstract 4417: Characterization of xenograft-derived EGFRvIII-positive GBM cell cultures reveals functional interactions between EGFRvIII, wild-type EGFR, and p53

Authors
Liu, I; Keir, S; Rasheed, BA; Bigner, D
MLA Citation
Liu, I, Keir, S, Rasheed, BA, and Bigner, D. "Abstract 4417: Characterization of xenograft-derived EGFRvIII-positive GBM cell cultures reveals functional interactions between EGFRvIII, wild-type EGFR, and p53." Cancer Research 71.8 Supplement (April 15, 2011): 4417-4417.
Source
crossref
Published In
Cancer Research
Volume
71
Issue
8 Supplement
Publish Date
2011
Start Page
4417
End Page
4417
DOI
10.1158/1538-7445.AM2011-4417

A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma.

Glioblastoma, the most common primary malignant brain tumor among adults, is a highly angiogenic and deadly tumor. Angiogenesis in glioblastoma, driven by hypoxia-dependent and independent mechanisms, is primarily mediated by vascular endothelial growth factor (VEGF), and generates blood vessels with distinctive features. The outcome for patients with recurrent glioblastoma is poor because of ineffective therapies. However, recent encouraging rates of radiographic response and progression-free survival, and adequate safety, led the FDA to grant accelerated approval of bevacizumab, a humanized monoclonal antibody against VEGF, for the treatment of recurrent glioblastoma in May 2009. These results have triggered significant interest in additional antiangiogenic agents and therapeutic strategies for patients with both recurrent and newly diagnosed glioblastoma. Given the potent antipermeability effect of VEGF inhibitors, the Radiologic Assessment in Neuro-Oncology (RANO) criteria were recently implemented to better assess response among patients with glioblastoma. Although bevacizumab improves survival and quality of life, eventual tumor progression is the norm. Better understanding of resistance mechanisms to VEGF inhibitors and identification of effective therapy after bevacizumab progression are currently a critical need for patients with glioblastoma.

Authors
Reardon, DA; Turner, S; Peters, KB; Desjardins, A; Gururangan, S; Sampson, JH; McLendon, RE; Herndon, JE; Jones, LW; Kirkpatrick, JP; Friedman, AH; Vredenburgh, JJ; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Turner, S, Peters, KB, Desjardins, A, Gururangan, S, Sampson, JH, McLendon, RE, Herndon, JE, Jones, LW, Kirkpatrick, JP, Friedman, AH, Vredenburgh, JJ, Bigner, DD, and Friedman, HS. "A review of VEGF/VEGFR-targeted therapeutics for recurrent glioblastoma." J Natl Compr Canc Netw 9.4 (April 2011): 414-427. (Review)
PMID
21464146
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
4
Publish Date
2011
Start Page
414
End Page
427

Monitoring radiographic brain tumor progression.

Determining radiographic progression in primary malignant brain tumors has posed a significant challenge to the neuroncology community. Glioblastoma multiforme (GBM, WHO Grade IV) through its inherent heterogeneous enhancement, growth patterns, and irregular nature has been difficult to assess for progression. Our ability to detect tumor progression radiographically remains inadequate. Despite the advanced imaging techniques, detecting tumor progression continues to be a clinical challenge. Here we review the different criteria used to detect tumor progression, and highlight the inherent challenges with detection of progression.

Authors
Mehta, AI; Kanaly, CW; Friedman, AH; Bigner, DD; Sampson, JH
MLA Citation
Mehta, AI, Kanaly, CW, Friedman, AH, Bigner, DD, and Sampson, JH. "Monitoring radiographic brain tumor progression." Toxins (Basel) 3.3 (March 2011): 191-200. (Review)
PMID
22069705
Source
pubmed
Published In
Toxins
Volume
3
Issue
3
Publish Date
2011
Start Page
191
End Page
200
DOI
10.3390/toxins3030191

Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma.

Epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific mutation widely expressed in glioblastoma multiforme (GBM) and other neoplasms, but absent from normal tissues. Immunotherapeutic targeting of EGFRvIII could eliminate neoplastic cells more precisely but may be inhibited by concurrent myelosuppressive chemotherapy like temozolomide (TMZ), which produces a survival benefit in GBM. A phase II, multicenter trial was undertaken to assess the immunogenicity of an experimental EGFRvIII-targeted peptide vaccine in patients with GBM undergoing treatment with serial cycles of standard-dose (STD) (200 mg/m(2) per 5 days) or dose-intensified (DI) TMZ (100 mg/m(2) per 21 days). All patients receiving STD TMZ exhibited at least a transient grade 2 lymphopenia, whereas those receiving DI TMZ exhibited a sustained grade 3 lymphopenia (<500 cells/μL). CD3(+) T-cell (P = .005) and B-cell (P = .004) counts were reduced significantly only in the DI cohort. Patients in the DI cohort had an increase in the proportion of immunosuppressive regulatory T cells (T(Reg); P = .008). EGFRvIII-specific immune responses developed in all patients treated with either regimen, but the DI TMZ regimen produced humoral (P = .037) and delayed-type hypersensitivity responses (P = .036) of greater magnitude. EGFRvIII-expressing tumor cells were also eradicated in nearly all patients (91.6%; CI(95): 64.0%-99.8%; P < .0001). The median progression-free survival (15.2 months; CI(95): 11.0-18.5 months; hazard ratio [HR] = 0.35; P = .024) and overall survival (23.6 months; CI(95): 18.5-33.1 months; HR = 0.23; P = .019) exceeded those of historical controls matched for entry criteria and adjusted for known prognostic factors. EGFRvIII-targeted vaccination induces patient immune responses despite therapeutic TMZ-induced lymphopenia and eliminates EGFRvIII-expressing tumor cells without autoimmunity.

Authors
Sampson, JH; Aldape, KD; Archer, GE; Coan, A; Desjardins, A; Friedman, AH; Friedman, HS; Gilbert, MR; Herndon, JE; McLendon, RE; Mitchell, DA; Reardon, DA; Sawaya, R; Schmittling, R; Shi, W; Vredenburgh, JJ; Bigner, DD; Heimberger, AB
MLA Citation
Sampson, JH, Aldape, KD, Archer, GE, Coan, A, Desjardins, A, Friedman, AH, Friedman, HS, Gilbert, MR, Herndon, JE, McLendon, RE, Mitchell, DA, Reardon, DA, Sawaya, R, Schmittling, R, Shi, W, Vredenburgh, JJ, Bigner, DD, and Heimberger, AB. "Greater chemotherapy-induced lymphopenia enhances tumor-specific immune responses that eliminate EGFRvIII-expressing tumor cells in patients with glioblastoma." Neuro Oncol 13.3 (March 2011): 324-333.
PMID
21149254
Source
pubmed
Published In
Neuro-Oncology
Volume
13
Issue
3
Publish Date
2011
Start Page
324
End Page
333
DOI
10.1093/neuonc/noq157

Imaging of convection enhanced delivery of toxins in humans.

Drug delivery of immunotoxins to brain tumors circumventing the blood brain barrier is a significant challenge. Convection-enhanced delivery (CED) circumvents the blood brain barrier through direct intracerebral application using a hydrostatic pressure gradient to percolate therapeutic compounds throughout the interstitial spaces of infiltrated brain and tumors. The efficacy of CED is determined through the distribution of the therapeutic agent to the targeted region. The vast majority of patients fail to receive a significant amount of coverage of the area at risk for tumor recurrence. Understanding this challenge, it is surprising that so little work has been done to monitor the delivery of therapeutic agents using this novel approach. Here we present a review of imaging in convection enhanced delivery monitoring of toxins in humans, and discuss future challenges in the field.

Authors
Mehta, AI; Choi, BD; Raghavan, R; Brady, M; Friedman, AH; Bigner, DD; Pastan, I; Sampson, JH
MLA Citation
Mehta, AI, Choi, BD, Raghavan, R, Brady, M, Friedman, AH, Bigner, DD, Pastan, I, and Sampson, JH. "Imaging of convection enhanced delivery of toxins in humans." Toxins (Basel) 3.3 (March 2011): 201-206. (Review)
PMID
22069706
Source
pubmed
Published In
Toxins
Volume
3
Issue
3
Publish Date
2011
Start Page
201
End Page
206
DOI
10.3390/toxins3030201

Compact point-detection fluorescence spectroscopy system for quantifying intrinsic fluorescence redox ratio in brain cancer diagnostics.

We report the development of a compact point-detection fluorescence spectroscopy system and two data analysis methods to quantify the intrinsic fluorescence redox ratio and diagnose brain cancer in an orthotopic brain tumor rat model. Our system employs one compact cw diode laser (407 nm) to excite two primary endogenous fluorophores, reduced nicotinamide adenine dinucleotide, and flavin adenine dinucleotide. The spectra were first analyzed using a spectral filtering modulation method developed previously to derive the intrinsic fluorescence redox ratio, which has the advantages of insensitivity to optical coupling and rapid data acquisition and analysis. This method represents a convenient and rapid alternative for achieving intrinsic fluorescence-based redox measurements as compared to those complicated model-based methods. It is worth noting that the method can also extract total hemoglobin concentration at the same time but only if the emission path length of fluorescence light, which depends on the illumination and collection geometry of the optical probe, is long enough so that the effect of absorption on fluorescence intensity due to hemoglobin is significant. Then a multivariate method was used to statistically classify normal tissues and tumors. Although the first method offers quantitative tissue metabolism information, the second method provides high overall classification accuracy. The two methods provide complementary capabilities for understanding cancer development and noninvasively diagnosing brain cancer. The results of our study suggest that this portable system can be potentially used to demarcate the elusive boundary between a brain tumor and the surrounding normal tissue during surgical resection.

Authors
Liu, Q; Grant, G; Li, J; Zhang, Y; Hu, F; Li, S; Wilson, C; Chen, K; Bigner, D; Vo-Dinh, T
MLA Citation
Liu, Q, Grant, G, Li, J, Zhang, Y, Hu, F, Li, S, Wilson, C, Chen, K, Bigner, D, and Vo-Dinh, T. "Compact point-detection fluorescence spectroscopy system for quantifying intrinsic fluorescence redox ratio in brain cancer diagnostics." J Biomed Opt 16.3 (March 2011): 037004-.
PMID
21456877
Source
pubmed
Published In
Journal of Biomedical Optics
Volume
16
Issue
3
Publish Date
2011
Start Page
037004
DOI
10.1117/1.3558840

Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome.

Point mutations of the NADP(+)-dependent isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) occur early in the pathogenesis of gliomas. When mutated, IDH1 and IDH2 gain the ability to produce the metabolite (R)-2-hydroxyglutarate (2HG), but the downstream effects of mutant IDH1 and IDH2 proteins or of 2HG on cellular metabolism are unknown. We profiled >200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants. Levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1- and IDH2-expressing cells. These changes were similar to those identified after treatment of the cells with 2HG. Remarkably, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants. NAAG also was significantly lower in human glioma tissues containing IDH mutations than in gliomas without such mutations. These metabolic changes provide clues to the pathogenesis of tumors associated with IDH gene mutations.

Authors
Reitman, ZJ; Jin, G; Karoly, ED; Spasojevic, I; Yang, J; Kinzler, KW; He, Y; Bigner, DD; Vogelstein, B; Yan, H
MLA Citation
Reitman, ZJ, Jin, G, Karoly, ED, Spasojevic, I, Yang, J, Kinzler, KW, He, Y, Bigner, DD, Vogelstein, B, and Yan, H. "Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome." Proc Natl Acad Sci U S A 108.8 (February 22, 2011): 3270-3275.
PMID
21289278
Source
pubmed
Published In
Proceedings of the National Academy of Sciences of USA
Volume
108
Issue
8
Publish Date
2011
Start Page
3270
End Page
3275
DOI
10.1073/pnas.1019393108

2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations.

BACKGROUND: Gliomas frequently contain mutations in the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase (IDH1) or the mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2). Several different amino acid substitutions recur at either IDH1 R132 or IDH2 R172 in glioma patients. Genetic evidence indicates that these mutations share a common gain of function, but it is unclear whether the shared function is dominant negative activity, neomorphic production of (R)-2-hydroxyglutarate (2HG), or both. METHODOLOGY/PRINCIPAL FINDINGS: We show by coprecipitation that five cancer-derived IDH1 R132 mutants bind IDH1-WT but that three cancer-derived IDH2 R172 mutants exert minimal binding to IDH2-WT. None of the mutants dominant-negatively lower isocitrate dehydrogenase activity at physiological (40 µM) isocitrate concentrations in mammalian cell lysates. In contrast to this, all of these mutants confer 10- to 100-fold higher 2HG production to cells, and glioma tissues containing IDH1 R132 or IDH2 R172 mutations contain high levels of 2HG compared to glioma tissues without IDH mutations (54.4 vs. 0.1 mg 2HG/g protein). CONCLUSIONS: Binding to, or dominant inhibition of, WT IDH1 or IDH2 is not a shared feature of the IDH1 and IDH2 mutations, and thus is not likely to be important in cancer. The fact that the gain of the enzymatic activity to produce 2HG is a shared feature of the IDH1 and IDH2 mutations suggests that this is an important function for these mutants in driving cancer pathogenesis.

Authors
Jin, G; Reitman, ZJ; Spasojevic, I; Batinic-Haberle, I; Yang, J; Schmidt-Kittler, O; Bigner, DD; Yan, H
MLA Citation
Jin, G, Reitman, ZJ, Spasojevic, I, Batinic-Haberle, I, Yang, J, Schmidt-Kittler, O, Bigner, DD, and Yan, H. "2-hydroxyglutarate production, but not dominant negative function, is conferred by glioma-derived NADP-dependent isocitrate dehydrogenase mutations. (Published online)" PLoS One 6.2 (February 4, 2011): e16812-.
PMID
21326614
Source
pubmed
Published In
PloS one
Volume
6
Issue
2
Publish Date
2011
Start Page
e16812
DOI
10.1371/journal.pone.0016812

Assessment of type of allergy and antihistamine use in the development of glioma.

BACKGROUND: Allergies have been associated with decreased risk of glioma; but, associations between duration and timing of allergies, and antihistamine use and glioma risk have been less consistent. The objective was to investigate this association by analyzing types, number, years since diagnosis, and age at diagnosis of allergies, and information on antihistamine usage, including type, duration, and frequency of exposure. METHODS: Self-report data on medically diagnosed allergies and antihistamine use were obtained for 419 glioma cases and 612 hospital-based controls from Duke University and NorthShore University HealthSystem. RESULTS: High- and low-grade glioma cases were statistically significantly less likely to report any allergy than controls (OR = 0.66, 95% CI: 0.49-0.87 and OR = 0.44, 95% CI: 0.25-0.76, respectively). The number of types of allergies (seasonal, medication, pet, food, and other) was inversely associated with glioma risk in a dose-response manner (P value for trend < 0.05). Age at diagnosis and years since diagnosis of allergies were not associated with glioma risk. Oral antihistamine use was statistically significantly inversely associated with glioma risk, but when stratified by allergy status, remained significant only for those with high-grade glioma and no medically diagnosed allergy. CONCLUSIONS: All types of allergies appear to be protective with reduced risk for those with more types of allergies. Antihistamine use, other than in relationship with allergy status, may not influence glioma risk. IMPACT: A comprehensive study of allergies and antihistamine use using standardized questions and biological markers will be essential to further delineate the biological mechanism that may be involved in brain tumor development.

Authors
McCarthy, BJ; Rankin, K; Il'yasova, D; Erdal, S; Vick, N; Ali-Osman, F; Bigner, DD; Davis, F
MLA Citation
McCarthy, BJ, Rankin, K, Il'yasova, D, Erdal, S, Vick, N, Ali-Osman, F, Bigner, DD, and Davis, F. "Assessment of type of allergy and antihistamine use in the development of glioma." Cancer Epidemiol Biomarkers Prev 20.2 (February 2011): 370-378.
PMID
21300619
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
20
Issue
2
Publish Date
2011
Start Page
370
End Page
378
DOI
10.1158/1055-9965.EPI-10-0948

Cellular redox modulator, ortho Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+) in the treatment of brain tumors.

Despite intensive efforts to improve multimodal treatment of brain tumor, survival remains limited. Current therapy consists of a combination of surgery, irradiation and chemotherapy with predisposition to long-term complications. Identifying novel targeted therapies is therefore at the forefront of brain tumor research. This study explores the utility of a manganese porphyrin in a brain tumor model. The compound used is ortho isomer, mangnese(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+). It is a powerful SOD mimic and peroxynitrite scavenger and a potent modulator of redox-based cellular transcriptional activity, able to suppress excessive immune and inflammatory responses and in turn proliferative pathways. It is further one of the most lipophilic compound among cationic Mn(III) N-alkylpyridylporphyrins, and thus accumulates predominantly in mitochondria relative to cytosol. In mitochondria, MnTnHex-2-PyP(5+) mimics our key antioxidant system, mitochondrial superoxide dismutase, MnSOD, whose overexpression has been widely shown to suppress tumor growth. Importantly, MnTnHex-2-PyP(5+) crosses blood brain barrier in sufficient amounts to demonstrate efficacy in treating CNS injuries. For those reasons we elected to test its effects in inhibiting brain tumor growth. This study is the first report of the antitumor properties of MnTnHex-2-PyP(5+) as a single agent in adult and pediatric glioblastoma multiforme (D-54 MG, D-245 MG, D-256 MG, D-456 MG) and pediatric medulloblastoma (D-341 MED), and is the first case where a redox-able metal complex has been used in glioma therapy. When given subcutaneously to mice bearing subcutaneous and intracranial xenografts, MnTnHex-2-PyP(5+) caused a significant (P ≤ 0.001) growth delay in D 245 MG, D-256 MG, D-341 MED, and D-456 MG tumors. Growth delay for mice bearing subcutaneous xenografts ranged from 3 days in D-54 MG to 34 days in D-341 MED. With mice bearing intracranial xenografts, MnTnHex-2-PyP(5+) increases median survival by 33% in adult glioblastoma multiforme (D-256 MG; p≤ 0.001) and 173% in pediatric medulloblastoma (D-341 MED, <0.001). The beneficial effects of MnTnHex-2-PyP(5+) are presumably achieved either (1) indirectly via elimination of signaling reactive oxygen and nitrogen species (in particular superoxide and peroxynitrite) which in turn would prevent activation of transcription factors; or (2) directly by coupling with cellular reductants and redox-sensitive signaling proteins. The former action is antioxidative while the latter action is presumably pro-oxidative in nature. Our findings suggest that the use of Mn porphyrin-based SOD mimics, and in particular lipophilic analogues such as MnTnHex-2-PyP(5+), is a promising approach for brain tumor therapy.

Authors
Keir, ST; Dewhirst, MW; Kirkpatrick, JP; Bigner, DD; Batinic-Haberle, I
MLA Citation
Keir, ST, Dewhirst, MW, Kirkpatrick, JP, Bigner, DD, and Batinic-Haberle, I. "Cellular redox modulator, ortho Mn(III) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin, MnTnHex-2-PyP(5+) in the treatment of brain tumors." Anticancer Agents Med Chem 11.2 (February 2011): 202-212.
PMID
21291403
Source
pubmed
Published In
Anti-Cancer Agents in Medicinal Chemistry
Volume
11
Issue
2
Publish Date
2011
Start Page
202
End Page
212

The genetic landscape of the childhood cancer medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor of children. To identify the genetic alterations in this tumor type, we searched for copy number alterations using high-density microarrays and sequenced all known protein-coding genes and microRNA genes using Sanger sequencing in a set of 22 MBs. We found that, on average, each tumor had 11 gene alterations, fewer by a factor of 5 to 10 than in the adult solid tumors that have been sequenced to date. In addition to alterations in the Hedgehog and Wnt pathways, our analysis led to the discovery of genes not previously known to be altered in MBs. Most notably, inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients. These results demonstrate key differences between the genetic landscapes of adult and childhood cancers, highlight dysregulation of developmental pathways as an important mechanism underlying MBs, and identify a role for a specific type of histone methylation in human tumorigenesis.

Authors
Parsons, DW; Li, M; Zhang, X; Jones, S; Leary, RJ; Lin, JC-H; Boca, SM; Carter, H; Samayoa, J; Bettegowda, C; Gallia, GL; Jallo, GI; Binder, ZA; Nikolsky, Y; Hartigan, J; Smith, DR; Gerhard, DS; Fults, DW; VandenBerg, S; Berger, MS; Marie, SKN; Shinjo, SMO; Clara, C; Phillips, PC; Minturn, JE; Biegel, JA; Judkins, AR; Resnick, AC; Storm, PB; Curran, T; He, Y; Rasheed, BA; Friedman, HS; Keir, ST; McLendon, R; Northcott, PA; Taylor, MD; Burger, PC; Riggins, GJ; Karchin, R; Parmigiani, G et al.
MLA Citation
Parsons, DW, Li, M, Zhang, X, Jones, S, Leary, RJ, Lin, JC-H, Boca, SM, Carter, H, Samayoa, J, Bettegowda, C, Gallia, GL, Jallo, GI, Binder, ZA, Nikolsky, Y, Hartigan, J, Smith, DR, Gerhard, DS, Fults, DW, VandenBerg, S, Berger, MS, Marie, SKN, Shinjo, SMO, Clara, C, Phillips, PC, Minturn, JE, Biegel, JA, Judkins, AR, Resnick, AC, Storm, PB, Curran, T, He, Y, Rasheed, BA, Friedman, HS, Keir, ST, McLendon, R, Northcott, PA, Taylor, MD, Burger, PC, Riggins, GJ, Karchin, R, and Parmigiani, G et al. "The genetic landscape of the childhood cancer medulloblastoma." Science 331.6016 (January 28, 2011): 435-439.
PMID
21163964
Source
pubmed
Published In
Science
Volume
331
Issue
6016
Publish Date
2011
Start Page
435
End Page
439
DOI
10.1126/science.1198056

A novel method for volumetric MRI response assessment of enhancing brain tumors.

Current radiographic response criteria for brain tumors have difficulty describing changes surrounding postoperative resection cavities. Volumetric techniques may offer improved assessment, however usually are time-consuming, subjective and require expert opinion and specialized magnetic resonance imaging (MRI) sequences. We describe the application of a novel volumetric software algorithm that is nearly fully automated and uses standard T1 pre- and post-contrast MRI sequences. T1-weighted pre- and post-contrast images are automatically fused and normalized. The tumor region of interest is grossly outlined by the user. An atlas of the nasal mucosa is automatically detected and used to normalize levels of enhancement. The volume of enhancing tumor is then automatically calculated. We tested the ability of our method to calculate enhancing tumor volume with resection cavity collapse and when the enhancing tumor is obscured by subacute blood in a resection cavity. To determine variability in results, we compared narrowly-defined tumor regions with tumor regions that include adjacent meningeal enhancement and also compared different contrast enhancement threshold levels used for the automatic calculation of enhancing tumor volume. Our method quantified enhancing tumor volume despite resection cavity collapse. It detected tumor volume increase in the midst of blood products that incorrectly caused decreased measurements by other techniques. Similar trends in volume changes across scans were seen with inclusion or exclusion of meningeal enhancement and despite different automated thresholds for tissue enhancement. Our approach appears to overcome many of the challenges with response assessment of enhancing brain tumors and warrants further examination and validation.

Authors
Kanaly, CW; Ding, D; Mehta, AI; Waller, AF; Crocker, I; Desjardins, A; Reardon, DA; Friedman, AH; Bigner, DD; Sampson, JH
MLA Citation
Kanaly, CW, Ding, D, Mehta, AI, Waller, AF, Crocker, I, Desjardins, A, Reardon, DA, Friedman, AH, Bigner, DD, and Sampson, JH. "A novel method for volumetric MRI response assessment of enhancing brain tumors. (Published online)" PLoS One 6.1 (January 26, 2011): e16031-.
PMID
21298088
Source
pubmed
Published In
PloS one
Volume
6
Issue
1
Publish Date
2011
Start Page
e16031
DOI
10.1371/journal.pone.0016031

Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma.

Sorafenib, an oral VEGFR-2, Raf, PDGFR, c-KIT and Flt-3 inhibitor, is active against renal cell and hepatocellular carcinomas, and has recently demonstrated promising activity for lung and breast cancers. In addition, various protracted temozolomide dosing schedules have been evaluated as a strategy to further enhance its anti-tumor activity. We reasoned that sorafenib and protracted, daily temozolomide may provide complementary therapeutic benefit, and therefore performed a phase 2 trial among recurrent glioblastoma patients. Adult glioblastoma patients at any recurrence after standard temozolomide chemoradiotherapy received sorafenib (400 mg twice daily) and continuous daily temozolomide (50 mg/m²/day). Assessments were performed every eight weeks. The primary endpoint was progression-free survival at 6 months (PFS-6) and secondary end points were radiographic response, overall survival (OS), safety and sorafenib pharmacokinetics. Of 32 enrolled patients, 12 (38%) were on CYP3-A inducing anti-epileptics (EIAEDs), 17 (53%) had 2 or more prior progressions, 15 had progressed while receiving 5-day temozolomide, and 12 (38%) had failed either prior bevacizumab or VEGFR inhibitor therapy. The most common grade ≥ 3 toxicities were palmer-planter erythrodysesthesia (19%) and elevated amylase/lipase (13%). Sorafenib pharmacokinetic exposures were comparable on day 1 regardless of EIAED status, but significantly lower on day 28 for patients on EIAEDs (P = 0.0431). With a median follow-up of 93 weeks, PFS-6 was 9.4%. Only one patient (3%) achieved a partial response. In conclusion, sorafenib can be safely administered with daily temozolomide, but this regimen has limited activity for recurrent GBM. Co-administration of EIAEDs can lower sorafenib exposures in this population.

Authors
Reardon, DA; Vredenburgh, JJ; Desjardins, A; Peters, K; Gururangan, S; Sampson, JH; Marcello, J; Herndon, JE; McLendon, RE; Janney, D; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Vredenburgh, JJ, Desjardins, A, Peters, K, Gururangan, S, Sampson, JH, Marcello, J, Herndon, JE, McLendon, RE, Janney, D, Friedman, AH, Bigner, DD, and Friedman, HS. "Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma." J Neurooncol 101.1 (January 2011): 57-66.
PMID
20443129
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
101
Issue
1
Publish Date
2011
Start Page
57
End Page
66
DOI
10.1007/s11060-010-0217-6

Reply to M.S. Lesniak

Authors
Mehta, AI; Persson, O; II, JEH; Archer, GE; McLendon, R; Heimberger, AB; Mitchell, DA; Bigner, DD; Sampson, JH
MLA Citation
Mehta, AI, Persson, O, II, JEH, Archer, GE, McLendon, R, Heimberger, AB, Mitchell, DA, Bigner, DD, and Sampson, JH. "Reply to M.S. Lesniak." Journal of Clinical Oncology 29.22 (2011): 3105-3106.
Source
scival
Published In
Journal of Clinical Oncology
Volume
29
Issue
22
Publish Date
2011
Start Page
3105
End Page
3106
DOI
10.1200/JCO.2011.35.0256

Reply to M.C. Chamberlain

Authors
Heimberger, AB; Bigner, DD; II, JEH; Sampson, JH
MLA Citation
Heimberger, AB, Bigner, DD, II, JEH, and Sampson, JH. "Reply to M.C. Chamberlain." Journal of Clinical Oncology 29.17 (2011): e519-e520.
Source
scival
Published In
Journal of Clinical Oncology
Volume
29
Issue
17
Publish Date
2011
Start Page
e519
End Page
e520
DOI
10.1200/JCO.2010.34.1453

Multiple phenotypic changes in mice after knockout of the B3gnt5 gene, encoding Lc3 synthase--a key enzyme in lacto-neolacto ganglioside synthesis.

BACKGROUND: Ganglioside biosynthesis occurs through a multi-enzymatic pathway which at the lactosylceramide step is branched into several biosynthetic series. Lc3 synthase utilizes a variety of galactose-terminated glycolipids as acceptors by establishing a glycosidic bond in the beta-1,3-linkage to GlcNaAc to extend the lacto- and neolacto-series gangliosides. In order to examine the lacto-series ganglioside functions in mice, we used gene knockout technology to generate Lc3 synthase gene B3gnt5-deficient mice by two different strategies and compared the phenotypes of the two null mouse groups with each other and with their wild-type counterparts. RESULTS: B3gnt5 gene knockout mutant mice appeared normal in the embryonic stage and, if they survived delivery, remained normal during early life. However, about 9% developed early-stage growth retardation, 11% died postnatally in less than 2 months, and adults tended to die in 5-15 months, demonstrating splenomegaly and notably enlarged lymph nodes. Without lacto-neolacto series gangliosides, both homozygous and heterozygous mice gradually displayed fur loss or obesity, and breeding mice demonstrated reproductive defects. Furthermore, B3gnt5 gene knockout disrupted the functional integrity of B cells, as manifested by a decrease in B-cell numbers in the spleen, germinal center disappearance, and less efficiency to proliferate in hybridoma fusion. CONCLUSIONS: These novel results demonstrate unequivocally that lacto-neolacto series gangliosides are essential to multiple physiological functions, especially the control of reproductive output, and spleen B-cell abnormality. We also report the generation of anti-IgG response against the lacto-series gangliosides 3'-isoLM1 and 3',6'-isoLD1.

Authors
Kuan, C-T; Chang, J; Mansson, J-E; Li, J; Pegram, C; Fredman, P; McLendon, RE; Bigner, DD
MLA Citation
Kuan, C-T, Chang, J, Mansson, J-E, Li, J, Pegram, C, Fredman, P, McLendon, RE, and Bigner, DD. "Multiple phenotypic changes in mice after knockout of the B3gnt5 gene, encoding Lc3 synthase--a key enzyme in lacto-neolacto ganglioside synthesis. (Published online)" BMC Dev Biol 10 (November 18, 2010): 114-.
Website
http://hdl.handle.net/10161/4341
PMID
21087515
Source
pubmed
Published In
BMC Developmental Biology
Volume
10
Publish Date
2010
Start Page
114
DOI
10.1186/1471-213X-10-114

Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma.

PURPOSE: Immunologic targeting of tumor-specific gene mutations may allow precise eradication of neoplastic cells without toxicity. Epidermal growth factor receptor variant III (EGFRvIII) is a constitutively activated and immunogenic mutation not expressed in normal tissues but widely expressed in glioblastoma multiforme (GBM) and other neoplasms. PATIENTS AND METHODS: A phase II, multicenter trial was undertaken to assess the immunogenicity of an EGFRvIII-targeted peptide vaccine and to estimate the progression-free survival (PFS) and overall survival (OS) of vaccinated patients with newly diagnosed EGFRvIII-expressing GBM with minimal residual disease. Intradermal vaccinations were given until toxicity or tumor progression was observed. Sample size was calculated to differentiate between PFS rates of 20% and 40% 6 months after vaccination. RESULTS: There were no symptomatic autoimmune reactions. The 6-month PFS rate after vaccination was 67% (95% CI, 40% to 83%) and after diagnosis was 94% (95% CI, 67% to 99%; n = 18). The median OS was 26.0 months (95% CI, 21.0 to 47.7 months). After adjustment for age and Karnofsky performance status, the OS of vaccinated patients was greater than that observed in a control group matched for eligibility criteria, prognostic factors, and temozolomide treatment (hazard ratio, 5.3; P = .0013; n = 17). The development of specific antibody (P = .025) or delayed-type hypersensitivity (P = .03) responses to EGFRvIII had a significant effect on OS. At recurrence, 82% (95% CI, 48% to 97%) of patients had lost EGFRvIII expression (P < .001). CONCLUSION: EGFRvIII-targeted vaccination in patients with GBM warrants investigation in a phase III, randomized trial.

Authors
Sampson, JH; Heimberger, AB; Archer, GE; Aldape, KD; Friedman, AH; Friedman, HS; Gilbert, MR; Herndon, JE; McLendon, RE; Mitchell, DA; Reardon, DA; Sawaya, R; Schmittling, RJ; Shi, W; Vredenburgh, JJ; Bigner, DD
MLA Citation
Sampson, JH, Heimberger, AB, Archer, GE, Aldape, KD, Friedman, AH, Friedman, HS, Gilbert, MR, Herndon, JE, McLendon, RE, Mitchell, DA, Reardon, DA, Sawaya, R, Schmittling, RJ, Shi, W, Vredenburgh, JJ, and Bigner, DD. "Immunologic escape after prolonged progression-free survival with epidermal growth factor receptor variant III peptide vaccination in patients with newly diagnosed glioblastoma." J Clin Oncol 28.31 (November 1, 2010): 4722-4729.
PMID
20921459
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
28
Issue
31
Publish Date
2010
Start Page
4722
End Page
4729
DOI
10.1200/JCO.2010.28.6963

Decoupling of DNA damage response signaling from DNA damages underlies temozolomide resistance in glioblastoma cells.

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor in adults. Current therapy includes surgery, radiation and chemotherapy with temozolomide (TMZ). Major determinants of clinical response to TMZ include methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter and mismatch repair (MMR) status. Though the MGMT promoter is methylated in 45% of cases, for the first nine months of follow-up, TMZ does not change survival outcome. Furthermore, MMR deficiency makes little contribution to clinical resistance, suggesting that there exist unrecognized mechanisms of resistance. We generated paired GBM cell lines whose resistance was attributed to neither MGMT nor MMR. We show that, responding to TMZ, these cells exhibit a decoupling of DNA damage response (DDR) from ongoing DNA damages. They display methylation-resistant synthesis in which ongoing DNA synthesis is not inhibited. They are also defective in the activation of the S and G2 phase checkpoint. DDR proteins ATM, Chk2, MDC1, NBS1 and gammaH2AX also fail to form discrete foci. These results demonstrate that failure of DDR may play an active role in chemoresistance to TMZ. DNA damages by TMZ are repaired by MMR proteins in a futile, reiterative process, which activates DDR signaling network that ultimately leads to the onset of cell death. GBM cells may survive genetic insults in the absence of DDR. We anticipate that our findings will lead to more studies that seek to further define the role of DDR in ultimately determining the fate of a tumor cell in response to TMZ and other DNA methylators.

Authors
Cui, B; Johnson, SP; Bullock, N; Ali-Osman, F; Bigner, DD; Friedman, HS
MLA Citation
Cui, B, Johnson, SP, Bullock, N, Ali-Osman, F, Bigner, DD, and Friedman, HS. "Decoupling of DNA damage response signaling from DNA damages underlies temozolomide resistance in glioblastoma cells." J Biomed Res 24.6 (November 2010): 424-435.
PMID
23554659
Source
pubmed
Published In
Journal of Biomedical Research
Volume
24
Issue
6
Publish Date
2010
Start Page
424
End Page
435
DOI
10.1016/S1674-8301(10)60057-7

Anti-EGFRvIII monoclonal antibody armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands.

INTRODUCTION: Monoclonal antibody (mAb) L8A4 binds specifically to the epidermal growth factor receptor variant III (EGFRvIII) that is present on gliomas but not on normal tissues, and is internalized rapidly after receptor binding. Because of the short range of its β-emissions, labeling this mAb with (177)Lu would be an attractive approach for the treatment of residual tumor margins remaining after surgical debulking of brain tumors. MATERIALS AND METHODS: L8A4 mAb was labeled with (177)Lu using the acyclic ligands [(R)-2-amino-3-(4-isothiocyanatophenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine-pentaacetic acid (CHX-A″-DTPA) and 2-(4-isothiocyanatobenzyl)-6-methyldiethylene-triaminepentaacetic acid (1B4M-DTPA), and the macrocyclic ligands S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-tetraacetic acid (C-DOTA) and α-(5-isothiocyanato-2-methoxyphenyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (MeO-DOTA). Paired-label tissue distribution experiments were performed in athymic mice bearing subcutaneous EGFRvIII-expressing U87.ΔEGFR glioma xenografts over a period of 1 to 8 days to directly compare (177)Lu-labeled L8A4 to L8A4 labeled with (125)I using N-succinimidyl 4-guanidinomethyl-3-[(125)I]iodobenzoate ([(125)I]SGMIB). RESULTS: Except with C-DOTA, tumor uptake for the (177)Lu-labeled mAb was significantly higher than the co-administered radioiodinated preparation; however, this was also the case for spleen, liver, bone and kidneys. Tumor/normal tissue ratios for (177)Lu-1B4M-DTPA-L8A4 and, to an even greater extent, (177)Lu-MeO-DOTA-L8A4 were higher than those for [(125)I]SGMIB-L8A4 in most other tissues. CONCLUSIONS: Tumor and normal tissue distribution patterns for this anti-EGFRvIII mAb were dependent on the nature of the bifunctional chelate used for (177)Lu labeling. Optimal results were obtained with 1B4M-DTPA and MeO-DOTA, suggesting no clear advantage for acyclic vs. macrocyclic ligands for this application.

Authors
Hens, M; Vaidyanathan, G; Zhao, X-G; Bigner, DD; Zalutsky, MR
MLA Citation
Hens, M, Vaidyanathan, G, Zhao, X-G, Bigner, DD, and Zalutsky, MR. "Anti-EGFRvIII monoclonal antibody armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands." Nucl Med Biol 37.7 (October 2010): 741-750.
PMID
20870149
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
37
Issue
7
Publish Date
2010
Start Page
741
End Page
750
DOI
10.1016/j.nucmedbio.2010.04.020

Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas.

Podoplanin/aggrus is a mucin-like sialoglycoprotein that is highly expressed in malignant gliomas. Podoplanin has been reported to be a novel marker to enrich tumor-initiating cells, which are thought to resist conventional therapies and to be responsible for cancer relapse. The purpose of this study was to determine whether an anti-podoplanin antibody is suitable to target radionuclides to malignant gliomas.The binding affinity of an anti-podoplanin antibody, NZ-1 (rat IgG(2a)), was determined by surface plasmon resonance and Scatchard analysis. NZ-1 was radioiodinated with (125)I using Iodogen [(125)I-NZ-1(Iodogen)] or N-succinimidyl 4-guanidinomethyl 3-[(131)I]iodobenzoate ([(131)I]SGMIB-NZ-1), and paired-label internalization assays of NZ-1 were performed. The tissue distribution of (125)I-NZ-1(Iodogen) and that of [(131)I]SGMIB-NZ-1 were then compared in athymic mice bearing glioblastoma xenografts.The dissociation constant (K(D)) of NZ-1 was determined to be 1.2 × 10(-10) M by surface plasmon resonance and 9.8 × 10(-10) M for D397MG glioblastoma cells by Scatchard analysis. Paired-label internalization assays in LN319 glioblastoma cells indicated that [(131)I]SGMIB-NZ-1 resulted in higher intracellular retention of radioactivity (26.3 ± 0.8% of initially bound radioactivity at 8 h) compared to that from the (125)I-NZ-1(Iodogen) (10.0 ± 0.1% of initially bound radioactivity at 8 h). Likewise, tumor uptake of [(131)I]SGMIB-NZ-1 (39.9 ± 8.8 %ID/g at 24 h) in athymic mice bearing D2159MG xenografts in vivo was significantly higher than that of (125)I-NZ-1(Iodogen) (29.7 ± 6.1 %ID/g at 24 h).The overall results suggest that an anti-podoplanin antibody NZ-1 warrants further evaluation for antibody-based therapy against glioblastoma.

Authors
Kato, Y; Vaidyanathan, G; Kaneko, MK; Mishima, K; Srivastava, N; Chandramohan, V; Pegram, C; Keir, ST; Kuan, C-T; Bigner, DD; Zalutsky, MR
MLA Citation
Kato, Y, Vaidyanathan, G, Kaneko, MK, Mishima, K, Srivastava, N, Chandramohan, V, Pegram, C, Keir, ST, Kuan, C-T, Bigner, DD, and Zalutsky, MR. "Evaluation of anti-podoplanin rat monoclonal antibody NZ-1 for targeting malignant gliomas." Nuclear medicine and biology 37.7 (October 2010): 785-794.
PMID
20870153
Source
epmc
Published In
Nuclear Medicine and Biology
Volume
37
Issue
7
Publish Date
2010
Start Page
785
End Page
794
DOI
10.1016/j.nucmedbio.2010.03.010

Epidermal growth factor receptor variant III mediates head and neck cancer cell invasion via STAT3 activation.

Epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) where aberrant signaling downstream of this receptor contributes to tumor growth. EGFR variant III (EGFRvIII) is the most commonly altered form of EGFR and contains a truncated ligand-binding domain. We previously reported that EGFRvIII is expressed in up to 40% of HNSCC tumors where it is associated with increased proliferation, tumor growth and chemoresistance to antitumor drugs including the EGFR-targeting monoclonal antibody cetuximab. Cetuximab was FDA-approved in 2006 for HNSCC but has not been shown to prevent invasion or metastasis. This study was undertaken to evaluate the mechanisms of EGFRvIII-mediated cell motility and invasion in HNSCC. We found that EGFRvIII induced HNSCC cell migration and invasion in conjunction with increased signal transducer and activator of transcription 3 (STAT3) activation, which was not abrogated by cetuximab treatment. Further investigation showed that EGF-induced expression of the STAT3 target gene HIF1-α, was abolished by cetuximab in HNSCC cells expressing wild-type EGFR under hypoxic conditions, but not in EGFRvIII-expressing HNSCC cells. These results suggest that EGFRvIII mediates HNSCC cell migration and invasion by increased STAT3 activation and induction of HIF1-α, which contribute to cetuximab resistance in EGFRvIII-expressing HNSCC tumors.

Authors
Wheeler, SE; Suzuki, S; Thomas, SM; Sen, M; Leeman-Neill, RJ; Chiosea, SI; Kuan, C-T; Bigner, DD; Gooding, WE; Lai, SY; Grandis, JR
MLA Citation
Wheeler, SE, Suzuki, S, Thomas, SM, Sen, M, Leeman-Neill, RJ, Chiosea, SI, Kuan, C-T, Bigner, DD, Gooding, WE, Lai, SY, and Grandis, JR. "Epidermal growth factor receptor variant III mediates head and neck cancer cell invasion via STAT3 activation." Oncogene 29.37 (September 16, 2010): 5135-5145.
PMID
20622897
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
29
Issue
37
Publish Date
2010
Start Page
5135
End Page
5145
DOI
10.1038/onc.2009.279

MRP3: a molecular target for human glioblastoma multiforme immunotherapy.

BACKGROUND: Glioblastoma multiforme (GBM) is refractory to conventional therapies. To overcome the problem of heterogeneity, more brain tumor markers are required for prognosis and targeted therapy. We have identified and validated a promising molecular therapeutic target that is expressed by GBM: human multidrug-resistance protein 3 (MRP3). METHODS: We investigated MRP3 by genetic and immunohistochemical (IHC) analysis of human gliomas to determine the incidence, distribution, and localization of MRP3 antigens in GBM and their potential correlation with survival. To determine MRP3 mRNA transcript and protein expression levels, we performed quantitative RT-PCR, raising MRP3-specific antibodies, and IHC analysis with biopsies of newly diagnosed GBM patients. We used univariate and multivariate analyses to assess the correlation of RNA expression and IHC of MRP3 with patient survival, with and without adjustment for age, extent of resection, and KPS. RESULTS: Real-time PCR results from 67 GBM biopsies indicated that 59/67 (88%) samples highly expressed MRP3 mRNA transcripts, in contrast with minimal expression in normal brain samples. Rabbit polyvalent and murine monoclonal antibodies generated against an extracellular span of MRP3 protein demonstrated reactivity with defined MRP3-expressing cell lines and GBM patient biopsies by Western blotting and FACS analyses, the latter establishing cell surface MRP3 protein expression. IHC evaluation of 46 GBM biopsy samples with anti-MRP3 IgG revealed MRP3 in a primarily membranous and cytoplasmic pattern in 42 (91%) of the 46 samples. Relative RNA expression was a strong predictor of survival for newly diagnosed GBM patients. Hazard of death for GBM patients with high levels of MRP3 RNA expression was 2.71 (95% CI: 1.54-4.80) times that of patients with low/moderate levels (p = 0.002). CONCLUSIONS: Human GBMs overexpress MRP3 at both mRNA and protein levels, and elevated MRP3 mRNA levels in GBM biopsy samples correlated with a higher risk of death. These data suggest that the tumor-associated antigen MRP3 has potential use for prognosis and as a target for malignant glioma immunotherapy.

Authors
Kuan, C-T; Wakiya, K; Herndon, JE; Lipp, ES; Pegram, CN; Riggins, GJ; Rasheed, A; Szafranski, SE; McLendon, RE; Wikstrand, CJ; Bigner, DD
MLA Citation
Kuan, C-T, Wakiya, K, Herndon, JE, Lipp, ES, Pegram, CN, Riggins, GJ, Rasheed, A, Szafranski, SE, McLendon, RE, Wikstrand, CJ, and Bigner, DD. "MRP3: a molecular target for human glioblastoma multiforme immunotherapy. (Published online)" BMC Cancer 10 (September 1, 2010): 468-.
Website
http://hdl.handle.net/10161/4357
PMID
20809959
Source
pubmed
Published In
BMC Cancer
Volume
10
Publish Date
2010
Start Page
468
DOI
10.1186/1471-2407-10-468

HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea.

Glioblastoma multiforme (GBM) is one of the deadliest tumors afflicting humans, and the mechanisms of its onset and progression remain largely undefined. Our attempts to elucidate its molecular pathogenesis through DNA copy-number analysis by genome-wide digital karyotyping and single nucleotide polymorphism arrays identified a dramatic focal amplification on chromosome 1q32 in 4 of 57 GBM tumors. Quantitative real-time PCR measurements revealed that HDMX is the most commonly amplified and overexpressed gene in the 1q32 locus. Further genetic screening of 284 low- and high-grade gliomas revealed that HDMX amplifications occur solely in pediatric and adult GBMs and that they are mutually exclusive of TP53 mutations and MDM2 amplifications. Here, we demonstrate that HDMX regulates p53 to promote GBM growth and attenuates tumor response to chemotherapy. In GBM cells, HDMX overexpression inhibits p53-mediated transcriptional activation of p21, releases cells from G0 to G1 phase, and enhances cellular proliferation. HDMX overexpression does not affect the expression of PUMA and BAX proapoptotic genes. While in GBM cells treated with the chemotherapeutic agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), HDMX appears to stabilize p53 and promote phosphorylation of the DNA double-stranded break repair protein H2AX, up-regulate the DNA repair gene VPX, stimulate DNA repair, and confer resistance to BCNU. In summary, HDMX exhibits bona fide oncogenic properties and offers a promising molecular target for GBM therapeutic intervention.

Authors
Jin, G; Cook, S; Cui, B; Chen, WC; Keir, ST; Killela, P; Di, C; Payne, CA; Gregory, SG; McLendon, R; Bigner, DD; Yan, H
MLA Citation
Jin, G, Cook, S, Cui, B, Chen, WC, Keir, ST, Killela, P, Di, C, Payne, CA, Gregory, SG, McLendon, R, Bigner, DD, and Yan, H. "HDMX regulates p53 activity and confers chemoresistance to 3-bis(2-chloroethyl)-1-nitrosourea." Neuro Oncol 12.9 (September 2010): 956-966.
PMID
20472715
Source
pubmed
Published In
Neuro-Oncology
Volume
12
Issue
9
Publish Date
2010
Start Page
956
End Page
966
DOI
10.1093/neuonc/noq045

Recombinant single-chain variable fragment antibodies against extracellular epitopes of human multidrug resistance protein MRP3 for targeting malignant gliomas.

Multidrug resistance protein 3 (MRP3), a multidrug resistance protein identified by serial analysis of gene expression as a glioblastoma multiforme (GBM)-associated molecule, is highly expressed in GBM, but not in normal brain cells. Thus, MRP3 is a candidate for GBM immunotargeting, but to date, no monoclonal antibody has been isolated that can target an extracellular MRP3 epitope. By phage display, we have isolated 3 recombinant, fully human, single-chain Fv (scFv) antibodies, M25, M58 and M89, which specifically react with the extracellular N-terminus of human MRP3. In ELISA, these scFvs reacted only with the peptide used for screening and not with other MRP3-derived peptides. Flow cytometric analysis revealed that these scFv fragments bind specifically to viable human GBM cells displaying different MRP3 expression levels, but not to MRP3-null cells. Furthermore, these scFv antibodies failed to react with tumor cells overexpressing other MRP proteins, including MRP1, MRP2, MRP4 and MRP5. M25 and M58 also bound to viable neurospheres. Iodogen-labeled scFvs demonstrated a yield of 56-76%. The immunoreactive fractions of the radiolabeled M25, M58 and M89 scFvs were 32, 52 and 69%, respectively. M25 exhibited 20% internalization into D2159MG neurospheres, M58, 33% into D54MG cells and M89, 26% into D247MG. Immunohistochemical evaluation of human gliomas to determine the localization of MRP3 antigen using scFvs M25 and M58 showed a dense cytoplasmic and membranous staining pattern. These Fv-based recombinant antibodies, which possess superior tumor penetration capabilities and selectively target tumor cells that express MRP3, may potentially be used in immunotherapy and diagnosis for brain tumors and other cancers.

Authors
Kuan, C-T; Srivastava, N; McLendon, RE; Marasco, WA; Zalutsky, MR; Bigner, DD
MLA Citation
Kuan, C-T, Srivastava, N, McLendon, RE, Marasco, WA, Zalutsky, MR, and Bigner, DD. "Recombinant single-chain variable fragment antibodies against extracellular epitopes of human multidrug resistance protein MRP3 for targeting malignant gliomas." Int J Cancer 127.3 (August 1, 2010): 598-611.
PMID
19937796
Source
pubmed
Published In
International Journal of Cancer
Volume
127
Issue
3
Publish Date
2010
Start Page
598
End Page
611
DOI
10.1002/ijc.25062

Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes.

The glioblastoma genome displays remarkable chromosomal aberrations, which harbor critical glioblastoma-specific genes contributing to several oncogenetic pathways. To identify glioblastoma-targeted genes, we completed a multifaceted genome-wide analysis to characterize the most significant aberrations of DNA content occurring in glioblastomas. We performed copy number analysis of 111 glioblastomas by Digital Karyotyping and Illumina BeadChip assays and validated our findings using data from the TCGA (The Cancer Genome Atlas) glioblastoma project. From this study, we identified recurrent focal copy number alterations in 1p36.23 and 4p16.3. Expression analyses of genes located in the two regions revealed genes which are dysregulated in glioblastomas. Specifically, we identify EGFR negative regulator, ERRFI1, within the minimal region of deletion in 1p36.23. In glioblastoma cells with a focal deletion of the ERRFI1 locus, restoration of ERRFI1 expression slowed cell migration. Furthermore, we demonstrate that TACC3, an Aurora-A kinase substrate, on 4p16.3, displays gain of copy number, is overexpressed in a glioma-grade-specific pattern, and correlates with Aurora kinase overexpression in glioblastomas. Our multifaceted genomic evaluation of glioblastoma establishes ERRFI1 as a potential candidate tumor suppressor gene and TACC3 as a potential oncogene, and provides insight on targets for oncogenic pathway-based therapy.

Authors
Duncan, CG; Killela, PJ; Payne, CA; Lampson, B; Chen, WC; Liu, J; Solomon, D; Waldman, T; Towers, AJ; Gregory, SG; McDonald, KL; McLendon, RE; Bigner, DD; Yan, H
MLA Citation
Duncan, CG, Killela, PJ, Payne, CA, Lampson, B, Chen, WC, Liu, J, Solomon, D, Waldman, T, Towers, AJ, Gregory, SG, McDonald, KL, McLendon, RE, Bigner, DD, and Yan, H. "Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes." Oncotarget 1.4 (August 2010): 265-277.
PMID
21113414
Source
pubmed
Published In
Oncotarget
Volume
1
Issue
4
Publish Date
2010
Start Page
265
End Page
277
DOI
10.18632/oncotarget.137

Targeted Radiotherapy of Central Nervous System Malignancies

Authors
Zalutsky, MR; Reardon, DA; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, and Bigner, DD. "Targeted Radiotherapy of Central Nervous System Malignancies." (July 15, 2010): 139-167. (Chapter)
Source
scopus
Publish Date
2010
Start Page
139
End Page
167
DOI
10.1002/9780470613214.ch5

IDH1(R132) mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain.

Isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2) are enzymes which convert isocitrate to alpha-ketoglutarate while reducing nicotinamide adenine dinucleotide phosphate (NADP+to NADPH). IDH1/2 were recently identified as mutated in a large percentage of progressive gliomas. These mutations occur at IDH1(R132) or the homologous IDH2(R172). Melanomas share some genetic features with IDH1/2-mutated gliomas, such as frequent TP53 mutation. We sought to test whether melanoma is associated with IDH1/2 mutations. Seventy-eight human melanoma samples were analyzed for IDH1(R132) and IDH2(R172) mutation status. A somatic, heterozygous IDH1 c.C394T (p.R132C) mutation was identified in one human melanoma metastasis to the lung. Having identified this mutation in one metastasis, we sought to test the hypothesis that certain selective pressures in the brain environment may specifically favor the cell growth or survival of tumor cells with mutations in IDH1/2, regardless of primary tumor site. To address this, we analyzed IDH1(R132) and IDH2(R172) mutation status 53 metastatic brain tumors, including nine melanoma metastases. Results revealed no mutations in any samples. This lack of mutations would suggest that mutations in IDH1(R132) or IDH2(R172) may be necessary for the formation of tumors in a cell-lineage dependent manner, with a particularly strong selective pressure for mutations in progressive gliomas; this also suggests the lack of a particular selective pressure for growth in brain tissue in general. Studies on the cell-lineages of tumors with IDH1/2 mutations may help clarify the role of these mutations in the development of brain tumors.

Authors
Lopez, GY; Reitman, ZJ; Solomon, D; Waldman, T; Bigner, DD; McLendon, RE; Rosenberg, SA; Samuels, Y; Yan, H
MLA Citation
Lopez, GY, Reitman, ZJ, Solomon, D, Waldman, T, Bigner, DD, McLendon, RE, Rosenberg, SA, Samuels, Y, and Yan, H. "IDH1(R132) mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain." Biochemical and biophysical research communications 398.3 (July 13, 2010): 585-587.
PMID
20603105
Source
epmc
Published In
Biochemical and Biophysical Research Communications
Volume
398
Issue
3
Publish Date
2010
Start Page
585
End Page
587
DOI
10.1016/j.bbrc.2010.06.125

IDH1 and IDH2 hotspot mutations are not found in canine glioma.

Authors
Reitman, ZJ; Olby, NJ; Mariani, CL; Thomas, R; Breen, M; Bigner, DD; McLendon, RE; Yan, H
MLA Citation
Reitman, ZJ, Olby, NJ, Mariani, CL, Thomas, R, Breen, M, Bigner, DD, McLendon, RE, and Yan, H. "IDH1 and IDH2 hotspot mutations are not found in canine glioma." Int J Cancer 127.1 (July 1, 2010): 245-246. (Letter)
PMID
19877121
Source
pubmed
Published In
International Journal of Cancer
Volume
127
Issue
1
Publish Date
2010
Start Page
245
End Page
246
DOI
10.1002/ijc.25017

Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1.

A major obstacle in glioblastoma (GBM) therapy is the restrictive nature of the blood-brain barrier (BBB). Convection-enhanced delivery (CED) is a novel method of drug administration which allows direct parenchymal infusion of therapeutics, bypassing the BBB. MR1-1 is a novel recombinant immunotoxin that targets the GBM tumor-specific antigen EGFRvIII and can be delivered via CED infusion. However, drug distribution via CED varies dramatically, which necessitates active monitoring. Gadolinium conjugated to diethylenetriamine penta-acetic acid (Gd-DTPA) is a commonly used MRI contrast agent which can be co-infused with therapies using CED and may be useful in monitoring infusion leak and early distribution. Forty immunocompetent rats were implanted with intracerebral cannulas that were connected to osmotic pumps and subsequently randomized into four groups that each received 0.2% human serum albumin (HSA) mixed with a different experimental infusion: (1) 25 ng/ml MR1-1; (2) 0.1 micromol/ml Gd-DTPA; (3) 25 ng/ml MR1-1 and 0.1 micromol/ml Gd-DTPA; (4) 250 ng/ml MR1-1 and 0.1 micromol/ml Gd-DTPA. The rats were monitored clinically for 6 weeks then necropsied and histologically assessed for CNS toxicity. All rats survived the entirety of the study without clinical or histological toxicity attributable to the study drugs. There was no statistically significant difference in weight change over time among groups (P > 0.999). MR1-1 co-infused with Gd-DTPA via CED is safe in the long-term setting in a pre-clinical animal model. Our data supports the use of Gd-DTPA, as a surrogate tracer, co-infused with MR1-1 for drug distribution monitoring in patients with GBM.

Authors
Ding, D; Kanaly, CW; Bigner, DD; Cummings, TJ; Herndon, JE; Pastan, I; Raghavan, R; Sampson, JH
MLA Citation
Ding, D, Kanaly, CW, Bigner, DD, Cummings, TJ, Herndon, JE, Pastan, I, Raghavan, R, and Sampson, JH. "Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1." J Neurooncol 98.1 (May 2010): 1-7.
PMID
19898744
Source
pubmed
Published In
Journal of Neuro-Oncology
Volume
98
Issue
1
Publish Date
2010
Start Page
1
End Page
7
DOI
10.1007/s11060-009-0046-7

OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas.

OTX2 is a developmentally regulated transcription factor involved in early morphogenesis of the central nervous system. This gene is amplified and overexpressed in medulloblastoma cell lines, but the nature and extent of its genetic alterations in primary tumors have not been evaluated. Analysis of a large cohort of primary medulloblastomas revealed frequent focal copy number gain of a region minimally containing OTX2 as a single gene. OTX2 copy number gain was restricted to tumor subtypes that did not express a molecular signature of Wnt or Shh pathway activation. FISH analysis revealed copy number gain in a subset of cells within medulloblastoma samples, suggesting a late event in tumor progression. Gain of OTX2 copy number was associated with the presence of anaplastic histologic features and shorter survival in medulloblastoma patients. In support of a functional role, ectopic OTX2 expression enhanced proliferation and tumorigenicity of immortalized primary cells, whereas OTX2 knockdown in medulloblastoma cells prolonged the survival of animals bearing xenograft tumors. Mechanistic investigations revealed upregulation of MYC as a potential mechanism whereby OTX2 promotes tumor progression. Our findings define OTX2 as an important oncogenic driver in medulloblastoma.

Authors
Adamson, DC; Shi, Q; Wortham, M; Northcott, PA; Di, C; Duncan, CG; Li, J; McLendon, RE; Bigner, DD; Taylor, MD; Yan, H
MLA Citation
Adamson, DC, Shi, Q, Wortham, M, Northcott, PA, Di, C, Duncan, CG, Li, J, McLendon, RE, Bigner, DD, Taylor, MD, and Yan, H. "OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas." Cancer Res 70.1 (January 1, 2010): 181-191.
PMID
20028867
Source
pubmed
Published In
Cancer Research
Volume
70
Issue
1
Publish Date
2010
Start Page
181
End Page
191
DOI
10.1158/0008-5472.CAN-09-2331

Genetic and epigenetic inactivation of Kruppel-like factor 4 in medulloblastoma.

Although medulloblastoma is the most common pediatric malignant brain tumor, its molecular underpinnings are largely unknown. We have identified rare, recurrent homozygous deletions of Kruppel-like Factor 4 (KLF4) in medulloblastoma using high-resolution single nucleotide polymorphism arrays, digital karyotyping, and genomic real-time polymerase chain reaction (PCR). Furthermore, we show that there is loss of physiological KLF4 expression in more than 40% of primary medulloblastomas both at the RNA and protein levels. Medulloblastoma cell lines drastically increase the expression of KLF4 in response to the demethylating agent 5-azacytidine and demonstrate dense methylation of the promoter CpG island by bisulfite sequencing. Methylation-specific PCR targeting the KLF4 promoter demonstrates CpG methylation in approximately 16% of primary medulloblastomas. Reexpression of KLF4 in the D283 medulloblastoma cell line results in significant growth suppression both in vitro and in vivo. We conclude that KLF4 is inactivated by either genetic or epigenetic mechanisms in a large subset of medulloblastomas and that it likely functions as a tumor suppressor gene in the pathogenesis of medulloblastoma.

Authors
Nakahara, Y; Northcott, PA; Li, M; Kongkham, PN; Smith, C; Yan, H; Croul, S; Ra, Y-S; Eberhart, C; Huang, A; Bigner, D; Grajkowska, W; Van Meter, T; Rutka, JT; Taylor, MD
MLA Citation
Nakahara, Y, Northcott, PA, Li, M, Kongkham, PN, Smith, C, Yan, H, Croul, S, Ra, Y-S, Eberhart, C, Huang, A, Bigner, D, Grajkowska, W, Van Meter, T, Rutka, JT, and Taylor, MD. "Genetic and epigenetic inactivation of Kruppel-like factor 4 in medulloblastoma." Neoplasia 12.1 (January 2010): 20-27.
PMID
20072650
Source
pubmed
Published In
Neoplasia (New York, N.Y.)
Volume
12
Issue
1
Publish Date
2010
Start Page
20
End Page
27

GMab-1, a high-affinity anti-3'-isoLM1/3',6'-isoLD1 IgG monoclonal antibody, raised in lacto-series ganglioside-defective knockout mice.

The lacto-series gangliosides 3'-isoLM1 and 3',6'-isoLD1 have been identified as tumor-associated antigens whose formation is initiated by the Lc3-synthase. Until now, high-affinity IgG monoclonal antibodies (mAbs) against 3'-isoLM1 and 3',6'-isoLD1, which are highly expressed in gliomas, have not been developed, although mAbs against lacto-series gangliosides are powerful tools for functional studies. We previously produced the Lc3-synthase gene beta3Gn-T5 knockout mice. In this study, we immunized beta3Gn-T5 knockout mice with 3'-isoLM1/3',6'-isoLD1 and produced the anti-3'-isoLM1/3',6'-isoLD1 mAb GMab-1, of the IgG(3) subclass, which should be useful for functional analysis of lacto-series gangliosides and for antibody-based therapy of gliomas.

Authors
Kato, Y; Kuan, C-T; Chang, J; Kaneko, MK; Ayriss, J; Piao, H; Chandramohan, V; Pegram, C; McLendon, RE; Fredman, P; Månsson, J-E; Bigner, DD
MLA Citation
Kato, Y, Kuan, C-T, Chang, J, Kaneko, MK, Ayriss, J, Piao, H, Chandramohan, V, Pegram, C, McLendon, RE, Fredman, P, Månsson, J-E, and Bigner, DD. "GMab-1, a high-affinity anti-3'-isoLM1/3',6'-isoLD1 IgG monoclonal antibody, raised in lacto-series ganglioside-defective knockout mice." Biochemical and biophysical research communications 391.1 (January 2010): 750-755.
PMID
19944071
Source
epmc
Published In
Biochemical and Biophysical Research Communications
Volume
391
Issue
1
Publish Date
2010
Start Page
750
End Page
755
DOI
10.1016/j.bbrc.2009.11.132

Central nervous system.

Several different types of tumors, benign and malignant, have been identified in the central nervous system (CNS). The prognoses for these tumors are related to several factors, such as the age of the patient and the location and histology of the tumor. In adults, about half of all CNS tumors are malignant, whereas in pediatric patients, more than 75% are malignant. For most benign CNS tumors that require treatment, neurosurgeons can offer curative resections or at least provide significant relief from mass effect. Unfortunately, we still lack effective treatments for most primary and secondary malignant CNS tumors. However, the past decade has witnessed an explosion in the understanding of the early molecular events in malignant primary CNS tumors, and for the first time in history, oncologists are seeing that a plethora of new therapies targeting these molecular events are being tested in clinical trials. There is hope on the horizon for the fight against these deadly tumors. The distribution of CNS tumors by location has remained constant for numerous years. The majority of primary CNS tumors arise in the major cortical lobes. Twenty nine percent of primary CNS tumors arise from the dural meninges that encase the CNS structures. The vast majority of these are meningiomas, of which over 90% are benign. About 10% of primary CNS tumors are found in the sella turcica region, where the pituitary gland resides. Other much less common sites of primary CNS tumors include the pineal region, ventricular system, cerebellum, brain stem, cranial nerves, and spinal cord. The distribution of CNS tumors by histology has seen a slight increase in more malignant tumors over the past decade, possibly due to increased neuroimaging practices or environmental exposures. Arising from glial cells, gliomas represent over 36% of all primary CNS tumors and consist of astrocytomas, oligodendrogliomas, ependymomas, mixed gliomas, and neuroepithelial tumors. The benign meningiomas make up 32% of primary CNS tumors, followed by nerve sheath tumors and pituitary tumors. Primary CNS lymphomas, embryonal tumors, and craniopharyngiomas are uncommon. The most common gliomas are astrocytomas, and these tumors are typically classified by the World Health Organization (WHO) as Grades I through IV. Grade IV, the most malignant grade of astrocytoma, includes glioblastoma multiforme (GBM), the most common malignant primary CNS glioma in adults, which represents 51% of all CNS gliomas. GBM is unfortunately the most challenging to effectively treat and has the worst patient survival. This chapter is therefore primarily devoted to the current understanding of this topic. Here we describe the molecular and cellular events associated with malignant glioma initiation and progression. We also review the importance of glioma stem cell biology and tumor immunology in early gliomagenesis. In addition, we present a brief description of the most common malignant primary CNS glioma in pediatric patients - medulloblastoma, as well as familial cancer syndromes that include gliomas as part of the syndrome.

Authors
Adamson, DC; Rasheed, BAK; McLendon, RE; Bigner, DD
MLA Citation
Adamson, DC, Rasheed, BAK, McLendon, RE, and Bigner, DD. "Central nervous system." Cancer Biomark 9.1-6 (2010): 193-210. (Review)
PMID
22112477
Source
pubmed
Published In
Cancer biomarkers : section A of Disease markers
Volume
9
Issue
1-6
Publish Date
2010
Start Page
193
End Page
210
DOI
10.3233/CBM-2011-0177

Erratum: Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1 (Journal of Neuro-Oncology DOI 10.1007/s11060-009-0046-7)

Authors
Ding, D; Kanaly, CW; Bigner, DD; Cummings, TJ; II, JEH; Pastan, I; Raghavan, R; Sampson, JH
MLA Citation
Ding, D, Kanaly, CW, Bigner, DD, Cummings, TJ, II, JEH, Pastan, I, Raghavan, R, and Sampson, JH. "Erratum: Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1 (Journal of Neuro-Oncology DOI 10.1007/s11060-009-0046-7)." Journal of Neuro-Oncology 98.1 (2010): 9--.
Source
scival
Published In
Journal of Neuro-Oncology
Volume
98
Issue
1
Publish Date
2010
Start Page
9-
DOI
10.1007/s11060-010-0183-z

A monoclonal antibody IMab-1 specifically recognizes IDH1R132H, the most common glioma-derived mutation.

IDH1 (isocitrate dehydrogenase 1) mutations have been identified as early and frequent genetic alterations in astrocytomas, oligodendrogliomas, and oligoastrocytomas as well as secondary glioblastomas. In contrast, primary glioblastomas very rarely contain IDH1 mutations, although primary and secondary glioblastomas are histologically indistinguishable. The IDH1 mutations are remarkably specific to a single codon in the conserved and functionally important Arg132 in IDH1. In gliomas, the most frequent IDH1 mutations (>90%) were G395A (R132H). In this study, we immunized mice with R132H-containing IDH1 (IDH1(R132H)) peptide. After cell fusion using Sendai virus envelope, the monoclonal antibodies (mAbs), which specifically reacted with IDH1(R132H), were screened in ELISA. One of the mAbs, IMab-1 reacted with the IDH1(R132H) peptide, but not with wild type IDH1 (IDH1(wt)) peptide in ELISA. In Western-blot analysis, IMab-1 reacted with only the IDH1(R132H) protein, not IDH1(wt) protein or the other IDH1 mutants, indicating that IMab-1 is IDH1(R132H)-specific. Furthermore, IMab-1 specifically stained the IDH1(R132H)-expressing cells in astrocytomas in immunohistochemistry, whereas it did not react with IDH1(R132H)-negative primary glioblastoma sections. In conclusion, we established an anti-IDH1(R132H)-specific monoclonal antibody IMab-1, which should be significantly useful for diagnosis and biological evaluation of mutation-bearing gliomas.

Authors
Kato, Y; Jin, G; Kuan, C-T; McLendon, RE; Yan, H; Bigner, DD
MLA Citation
Kato, Y, Jin, G, Kuan, C-T, McLendon, RE, Yan, H, and Bigner, DD. "A monoclonal antibody IMab-1 specifically recognizes IDH1R132H, the most common glioma-derived mutation." Biochem Biophys Res Commun 390.3 (December 18, 2009): 547-551.
PMID
19818334
Source
pubmed
Published In
Biochemical and Biophysical Research Communications
Volume
390
Issue
3
Publish Date
2009
Start Page
547
End Page
551
DOI
10.1016/j.bbrc.2009.10.001

Mutant metabolic enzymes are at the origin of gliomas.

Mutations of the isocitrate dehydrogenase (IDH) metabolic enzymes IDH1 and IDH2 have been found to be frequent and early genetic alterations in astrocytomas and oligodendrogliomas. All mutations identified to date affect a single amino acid located within the isocitrate binding site (R132 of IDH1 and the analogous R172 residue of IDH2). IDH1 and IDH2 mutations define a specific subtype of gliomas and may have significant utility for the diagnosis, prognosis, and treatment of patients with these tumors.

Authors
Yan, H; Bigner, DD; Velculescu, V; Parsons, DW
MLA Citation
Yan, H, Bigner, DD, Velculescu, V, and Parsons, DW. "Mutant metabolic enzymes are at the origin of gliomas." Cancer Res 69.24 (December 15, 2009): 9157-9159. (Review)
PMID
19996293
Source
pubmed
Published In
Cancer Research
Volume
69
Issue
24
Publish Date
2009
Start Page
9157
End Page
9159
DOI
10.1158/0008-5472.CAN-09-2650

Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study.

BACKGROUND: We evaluated bevacizumab with metronomic etoposide among recurrent malignant glioma patients in a phase 2, open-label trial. METHODS: A total of 59 patients, including 27 with glioblastoma (GBM) and 32 with grade 3 malignant glioma, received 10 mg kg(-1) bevacizumab biweekly and 50 mg m(-2) etoposide daily for 21 consecutive days each month. The primary end point was a 6-month progression-free survival, and secondary end points included safety and overall survival. Vascular endothelial growth factor (VEGF), VEGFR-2, carbonic anhydrase 9 (CA9) and hypoxia-inducible factor-2alpha (HIF-2alpha) were assessed semiquantitatively in archival tumours using immunohistochemistry and were correlated with outcome. RESULTS: Among grade 3 and GBM patients, the 6-month progression-free survivals were 40.6% and 44.4%, the radiographic response rates were 22% and 37% and the median survivals were 63.1 and 44.4 weeks, respectively. Hypertension predicted better outcome among both grade 3 and GBM patients, whereas high CA9 and low VEGF were associated with poorer progression-free survival (PFS) among those with GBM. The most common grade > or = 3 adverse events included neutropaenia (24%), thrombosis (12%), infection (8%) and hypertension (3%). Two patients had asymptomatic, grade 1 intracranial haemorrhage and one on-study death occurred because of pulmonary embolism. CONCLUSION: Bevacizumab with metronomic etoposide has increased toxicity compared with previous reports of bevacizumab monotherapy. Its anti-tumour activity is similar to that of bevacizumab monotherapy or bevacizumab plus irinotecan. (ClinicalTrials.gov: NCT00612430).

Authors
Reardon, DA; Desjardins, A; Vredenburgh, JJ; Gururangan, S; Sampson, JH; Sathornsumetee, S; McLendon, RE; Herndon, JE; Marcello, JE; Norfleet, J; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Desjardins, A, Vredenburgh, JJ, Gururangan, S, Sampson, JH, Sathornsumetee, S, McLendon, RE, Herndon, JE, Marcello, JE, Norfleet, J, Friedman, AH, Bigner, DD, and Friedman, HS. "Metronomic chemotherapy with daily, oral etoposide plus bevacizumab for recurrent malignant glioma: a phase II study." Br J Cancer 101.12 (December 15, 2009): 1986-1994.
PMID
19920819
Source
pubmed
Published In
British Journal of Cancer
Volume
101
Issue
12
Publish Date
2009
Start Page
1986
End Page
1994
DOI
10.1038/sj.bjc.6605412

Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress.

Glioblastoma multiforme is the most prevalent type of adult brain tumor and one of the deadliest tumors known to mankind. The genetic understanding of glioblastoma multiforme is, however, limited, and the molecular mechanisms that facilitate glioblastoma multiforme cell survival and growth within the tumor microenvironment are largely unknown. We applied digital karyotyping and single nucleotide polymorphism arrays to screen for copy-number changes in glioblastoma multiforme samples and found that the most frequently amplified region is at chromosome 7p11.2. The high resolution of digital karyotyping and single nucleotide polymorphism arrays permits the precise delineation of amplicon boundaries and has enabled identification of the minimal region of amplification at chromosome 7p11.2, which contains two genes, EGFR and SEC61gamma. SEC61gamma encodes a subunit of a heterotrimeric protein channel located in the endoplasmic reticulum (ER). In addition to its high frequency of gene amplification in glioblastoma multiforme, SEC61gamma is also remarkably overexpressed in 77% of glioblastoma multiforme but not in lower-grade gliomas. The small interfering RNA-mediated knockdown of SEC61gamma expression in tumor cells led to growth suppression and apoptosis. Furthermore, we showed that pharmacologic ER stress agents induce SEC61gamma expression in glioblastoma multiforme cells. Together, these results indicate that aberrant expression of SEC61gamma serves significant roles in glioblastoma multiforme cell survival likely via a mechanism that is involved in the cytoprotective ER stress-adaptive response to the tumor microenvironment.

Authors
Lu, Z; Zhou, L; Killela, P; Rasheed, AB; Di, C; Poe, WE; McLendon, RE; Bigner, DD; Nicchitta, C; Yan, H
MLA Citation
Lu, Z, Zhou, L, Killela, P, Rasheed, AB, Di, C, Poe, WE, McLendon, RE, Bigner, DD, Nicchitta, C, and Yan, H. "Glioblastoma proto-oncogene SEC61gamma is required for tumor cell survival and response to endoplasmic reticulum stress." Cancer Res 69.23 (December 1, 2009): 9105-9111.
PMID
19920201
Source
pubmed
Published In
Cancer Research
Volume
69
Issue
23
Publish Date
2009
Start Page
9105
End Page
9111
DOI
10.1158/0008-5472.CAN-09-2775

Detection of amino-terminal extracellular domain of somatostatin receptor 2 by specific monoclonal antibodies and quantification of receptor density in medulloblastoma.

Somatostatin receptor 2 (SSTR2) is expressed by most medulloblastomas (MEDs). We isolated monoclonal antibodies (MAbs) to the 12-mer (33)QTEPYYDLTSNA(44), which resides in the extracellular domain of the SSTR2 amino terminus, screened the peptide-bound MAbs by fluorescence microassay on D341 and D283 MED cells, and demonstrated homogeneous cell-surface binding, indicating that all cells expressed cell surface-detectable epitopes. Five radiolabeled MAbs were tested for immunoreactive fraction (IRF), affinity (KA) (Scatchard analysis vs. D341 MED cells), and internalization by MED cells. One IgG(3) MAb exhibited a 50-100% IRF, but low KA. Four IgG(2a) MAbs had 46-94% IRFs and modest KAs versus intact cells (0.21-1.2 x 10(8) M(-1)). Following binding of radiolabeled MAbs to D341 MED at 4 degrees C, no significant internalization was observed, which is consistent with results obtained in the absence of ligand. However, all MAbs exhibited long-term association with the cells; binding at 37 degrees C after 2 h was 65-66%, and after 24 h, 52-64%. In tests with MAbs C10 and H5, the number of cell surface receptors per cell, estimated by Scatchard and quantitative FACS analyses, was 3.9 x 10(4) for the "glial" phenotype DAOY MED cell line and 0.6-8.8 x 10(5) for four neuronal phenotype MED cell lines. Our results indicate a potential immunotherapeutic application for these MAbs.

Authors
Kuan, C-T; Wikstrand, CJ; McLendon, RE; Zalutsky, MR; Kumar, U; Bigner, DD
MLA Citation
Kuan, C-T, Wikstrand, CJ, McLendon, RE, Zalutsky, MR, Kumar, U, and Bigner, DD. "Detection of amino-terminal extracellular domain of somatostatin receptor 2 by specific monoclonal antibodies and quantification of receptor density in medulloblastoma." Hybridoma (Larchmt) 28.6 (December 2009): 389-403.
Website
http://hdl.handle.net/10161/3241
PMID
20025498
Source
pubmed
Published In
Hybridoma
Volume
28
Issue
6
Publish Date
2009
Start Page
389
End Page
403
DOI
10.1089/hyb.2009.0049

GENETIC DIVERSITY ASSOCIATED WITH SURVIVAL IN MALIGNANT GLIOMAS IDENTIFIED BY LINKAGE DISEQUILIBRIUM-BASED ANALYSIS OF HAPLOTYPE BLOCK REGIONS OF DNA REPAIR GENES

Authors
Ali-Osman, F; Owzar, K; Adams, B; Lipp, E; Herdon, J; Illyasova, D; Davis, F; Vick, N; Friedman, A; McClendon, R; Reardon, D; Friedman, H; Weale, M; Bigner, D
MLA Citation
Ali-Osman, F, Owzar, K, Adams, B, Lipp, E, Herdon, J, Illyasova, D, Davis, F, Vick, N, Friedman, A, McClendon, R, Reardon, D, Friedman, H, Weale, M, and Bigner, D. "GENETIC DIVERSITY ASSOCIATED WITH SURVIVAL IN MALIGNANT GLIOMAS IDENTIFIED BY LINKAGE DISEQUILIBRIUM-BASED ANALYSIS OF HAPLOTYPE BLOCK REGIONS OF DNA REPAIR GENES." December 2009.
Source
wos-lite
Published In
Neuro-Oncology
Volume
11
Issue
6
Publish Date
2009
Start Page
891
End Page
891

Heat shock protein 70-binding protein 1 is highly expressed in high-grade gliomas, interacts with multiple heat shock protein 70 family members, and specifically binds brain tumor cell surfaces.

Chaperone proteins and heat shock proteins (HSP) are essential components of cellular protein folding systems under normal conditions; their expression and activities are upregulated during stress. Chronically stressed tumors frequently exhibit high chaperone protein levels, exploiting their anti-apoptotic mechanisms and general proteome homeostasis amidst a background of genetic instability. Co-chaperones interact with chaperones as malleable regulatory components of protein folding activity and may represent a conduit for modification of chaperone activity to the detriment of the tumor. We have initially characterized one such co-chaperone, heat shock protein 70-binding protein (HspBP) 1 from human brain tumors, their xenografts grown in immune-compromised mice, and in syngeneic murine models in immune-competent mice. Immunohistochemical analyses show HspBP1 overexpression (with unusual subcellular localizations) in patient brain tumors relative to normal brain tissue. This holds true for the xenograft and syngeneic murine tumor models. In biochemical affinity chromatography assays, HspBP1 interacts with members of the HSP70 family from brain tumor lysates and from surface-derived samples, including HSP70, glucose regulated protein (GRP)75, GRP78, and HSP110. From normal brain lysates, only heat shock cognate (HSC)70, GRP75, and HSP110 bind to HspBP1. FACS analyses indicate that HspBP1 binds to brain tumor cell surfaces, possibly via HSP70 family members, and internalizes into cells. This has implications for HspBP1 biology as well as its utility as a tumor-targeting agent. Our results suggest that HspBP1 may play a role in tumor (dys)regulation of chaperone proteins, and that HspBP1 may have extracellular roles with therapeutic implications.

Authors
Graner, MW; Raynes, DA; Bigner, DD; Guerriero, V
MLA Citation
Graner, MW, Raynes, DA, Bigner, DD, and Guerriero, V. "Heat shock protein 70-binding protein 1 is highly expressed in high-grade gliomas, interacts with multiple heat shock protein 70 family members, and specifically binds brain tumor cell surfaces." Cancer Sci 100.10 (October 2009): 1870-1879.
PMID
19659607
Source
pubmed
Published In
Cancer Science
Volume
100
Issue
10
Publish Date
2009
Start Page
1870
End Page
1879
DOI
10.1111/j.1349-7006.2009.01269.x

A sphingosine kinase inhibitor induces cell death in temozolomide resistant glioblastoma cells.

PURPOSE: Sphingosine kinase is an oncogene that is up-regulated in several solid tumors. The product of the sphingosine kinase activity, sphingosine-1-phosphate is a potent mitogen involved in diverse cell processes such as cell survival and migration. Current standard therapy in the treatment of glioblastoma multiforme (GBM) is a combination of surgery, radiation, and chemotherapy using the drug temozolomide (TMZ). However, virtually all tumors become resistant to TMZ. Therefore, new drug targets are necessary. In this study, we investigated whether inhibiting sphingosine kinase could induce cell death in TMZ-resistant GBM cells. METHODS: To study TMZ resistance in vitro, we have generated TMZ-resistant cell lines from established GBM cells. We used a potent inhibitor of sphingosine kinase to study its effect on colony formation and cell growth in GBM cells with a limited dilution and WST assay. Moreover, cell death was determined by measuring caspase-3 activity using flow cytometry. RESULTS: A sphingosine kinase inhibitor reduced cell colony formation and activated caspase-3 in both TMZ-sensitive and resistant GBM cells. CONCLUSION: Addition of a sphingosine kinase inhibitor to the standard chemotherapy regimen against GBM may be beneficial.

Authors
Bektas, M; Johnson, SP; Poe, WE; Bigner, DD; Friedman, HS
MLA Citation
Bektas, M, Johnson, SP, Poe, WE, Bigner, DD, and Friedman, HS. "A sphingosine kinase inhibitor induces cell death in temozolomide resistant glioblastoma cells." Cancer Chemother Pharmacol 64.5 (October 2009): 1053-1058.
PMID
19597728
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
64
Issue
5
Publish Date
2009
Start Page
1053
End Page
1058
DOI
10.1007/s00280-009-1063-0

EGFRvIII-targeted vaccination therapy of malignant glioma.

Given the highly infiltrative growth pattern of malignant glioma and the lack of specificity associated with currently available treatment regimens, alternative strategies designed to eradicate cancer cells while limiting collateral toxicity in normal tissues remain a high priority. To this end, the development of specific immunotherapies against targeted neoplastic cells represents a promising approach. The epidermal growth factor receptor class III variant (EGFRvIII), a constitutively activated mutant of the wild-type tyrosine kinase, is present in a substantial proportion of malignant gliomas and other human cancers, yet completely absent from normal tissues. This receptor variant consists of an in-frame deletion, the translation of which produces an extracellular junction with a novel glycine residue, flanked by amino acid sequences that are not typically adjacent in the normal protein. In this review, both preclinical and early clinical development of a peptide vaccine directed against this portion of the EGFRvIII antigenic domain are recapitulated. Following vaccination, our group has demonstrated potent, redirected cellular and humoral immunity against cancer cells expressing the mutant receptor without significant toxicity. Additionally, the corresponding therapeutic outcomes observed in these studies lend credence to the potential role of peptide-based vaccination strategies among emerging antitumor immunotherapies in patients with malignant glioma.

Authors
Choi, BD; Archer, GE; Mitchell, DA; Heimberger, AB; McLendon, RE; Bigner, DD; Sampson, JH
MLA Citation
Choi, BD, Archer, GE, Mitchell, DA, Heimberger, AB, McLendon, RE, Bigner, DD, and Sampson, JH. "EGFRvIII-targeted vaccination therapy of malignant glioma." Brain Pathol 19.4 (October 2009): 713-723. (Review)
PMID
19744042
Source
pubmed
Published In
Brain Pathology
Volume
19
Issue
4
Publish Date
2009
Start Page
713
End Page
723
DOI
10.1111/j.1750-3639.2009.00318.x

An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme.

Conventional therapies for glioblastoma multiforme (GBM) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by nonspecific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent and tumor-specific mutation widely expressed in GBMs and other neoplasms. The safety and immunogenicity of a dendritic cell (DC)-based vaccine targeting the EGFRvIII antigen was evaluated in this study. Adults with newly diagnosed GBM, who had undergone gross-total resection and standard conformal external beam radiotherapy, received three consecutive intradermal vaccinations with autologous mature DCs pulsed with an EGFRvIII-specific peptide conjugated to keyhole limpet hemocyanin. The dose of DCs was escalated in cohorts of three patients. Patients were monitored for toxicity, immune response, radiographic and clinical progression, and death. No allergic reactions or serious adverse events were seen. Adverse events were limited to grade 2 toxicities. The maximum feasible dose of antigen-pulsed mature DCs was reached at 5.7 x 10(7) +/- 2.9 x 10(7) SD without dose-limiting toxicity. EGFRvIII-specific immune responses were evident in most patients. The mean time from histologic diagnosis to vaccination was 3.6 +/- 0.6 SD months. Median time to progression from vaccination was 6.8 months [95% confidence interval (C.I.(95)), 2.5-8.8], and median survival time from vaccination was 18.7 months (C.I.(95), 14.5-25.6). Overall median survival from time of histologic diagnosis was 22.8 months (C.I.(95), 17.5-29). This study establishes the EGFRvIII mutation as a safe and immunogenic tumor-specific target for immunotherapy.

Authors
Sampson, JH; Archer, GE; Mitchell, DA; Heimberger, AB; Herndon, JE; Lally-Goss, D; McGehee-Norman, S; Paolino, A; Reardon, DA; Friedman, AH; Friedman, HS; Bigner, DD
MLA Citation
Sampson, JH, Archer, GE, Mitchell, DA, Heimberger, AB, Herndon, JE, Lally-Goss, D, McGehee-Norman, S, Paolino, A, Reardon, DA, Friedman, AH, Friedman, HS, and Bigner, DD. "An epidermal growth factor receptor variant III-targeted vaccine is safe and immunogenic in patients with glioblastoma multiforme." Mol Cancer Ther 8.10 (October 2009): 2773-2779.
PMID
19825799
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
8
Issue
10
Publish Date
2009
Start Page
2773
End Page
2779
DOI
10.1158/1535-7163.MCT-09-0124

Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma.

This phase I clinical trial conducted with patients who had recurrent or progressive malignant glioma (MG) was designed to determine the maximum tolerated dose (MTD) and toxicity of three different 5-day dosing regimens of temozolomide (TMZ) in combination with O(6)-benzylguanine (O(6)-BG). Both TMZ and O(6)-BG were administered on days 1-5 of a 28-day treatment cycle. A bolus infusion of O(6)-BG was administered at 120 mg/m(2) over 1 h on days 1, 3, and 5, along with a continuous infusion of O(6)-BG at 30 mg/m(2)/day. TMZ was administered at the end of the first bolus infusion of O(6)-BG and then every 24 h for 5 days during the continuous infusion of O(6)-BG. Patients were accrued to one of three 5-day dosing regimens of TMZ. Twenty-nine patients were enrolled into this study. The dose-limiting toxicities (DLTs) were grade 4 neutropenia, leukopenia, and thrombocytopenia. The MTD for TMZ for the three different 5-day dosing schedules was determined as follows: schedule 1, 200 mg/m(2) on day 1 and 50 mg/m(2)/day on days 2-5; schedule 2, 50 mg/m(2)/day on days 1-5; and schedule 3, 50 mg/m(2)/day on days 1-5 while receiving pegfilgrastim. Thus, the 5-day TMZ dosing schedule that maximized the total dose of TMZ when combined with O(6)-BG was schedule 1. This study provides the foundation for a phase II trial of O(6)-BG in combination with a 5-day dosing schedule of TMZ in TMZ-resistant MG.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Walker, A; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Rich, JN, Gururangan, S, Friedman, AH, Bigner, DD, Sampson, JH, McLendon, RE, Herndon, JE, Walker, A, and Friedman, HS. "Phase I trial of temozolomide plus O6-benzylguanine 5-day regimen with recurrent malignant glioma." Neuro Oncol 11.5 (October 2009): 556-561.
PMID
19289491
Source
pubmed
Published In
Neuro-Oncology
Volume
11
Issue
5
Publish Date
2009
Start Page
556
End Page
561
DOI
10.1215/15228517-2009-007

Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy.

BACKGROUND: Glioblastoma multiforme (GBM), the most lethal type of brain tumor, has a 1-year median survival. The effect of carmustine wafers on the survival of newly diagnosed GBM patients treated with radiotherapy (RT) and concurrent temozolomide (TMZ) plus RT plus rotational chemotherapy was investigated. METHODS: An institutional review board-approved retrospective study was conducted in 85 newly diagnosed GBM patients who received surgical resection with and without carmustine wafers followed by RT and concurrent TMZ plus rotational chemotherapy. Treatment group comparisons were conducted using the log-rank test. Survival experience of the Duke cohort was examined within specific patient subgroups defined by the original Radiation Therapy Oncology Group (RTOG) recursive partition analysis (RPA) class and compared with the European Organization for Research and Treatment of Cancer (Stupp) and RTOG trial. RESULTS: Overall 1- and 2-year survival for the noncarmustine wafer cohort were 69% and 29%, respectively, with a median survival of 72.7 weeks. One- and 2-year survival for the carmustine wafer cohort were 81% and 47%, with median survival of 89.5 weeks. Carmustine wafer was not an independent predictor (P=.110) of survival after adjustment for RPA class. The proportion of patients in the carmustine wafer cohort who lived longer than predicted based upon Stupp regimen results was significantly greater than 0.5 (P<.006); similar results based upon the RTOG trial data were observed (P<.001). CONCLUSIONS: Carmustine wafer with concurrent TMZ and radiation followed by rotational chemotherapy is a well tolerated, effective therapy, and has a survival benefit compared with radiation alone. Prospective randomized trials are needed to rigorously compare the carmustine wafer regimen to the Stupp and postradiation multimodality regimens.

Authors
Affronti, ML; Heery, CR; Herndon, JE; Rich, JN; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Affronti, ML, Heery, CR, Herndon, JE, Rich, JN, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Friedman, AH, Bigner, DD, and Friedman, HS. "Overall survival of newly diagnosed glioblastoma patients receiving carmustine wafers followed by radiation and concurrent temozolomide plus rotational multiagent chemotherapy." Cancer 115.15 (August 1, 2009): 3501-3511.
PMID
19514083
Source
pubmed
Published In
Cancer
Volume
115
Issue
15
Publish Date
2009
Start Page
3501
End Page
3511
DOI
10.1002/cncr.24398

Glioblastoma multiforme: a review of where we have been and where we are going.

Malignant gliomas such as glioblastoma multiforme (GBM) present some of the greatest challenges in the management of cancer patients worldwide, despite notable recent achievements in oncology. Even with aggressive surgical resections using state-of-the-art preoperative and intraoperative neuroimaging, along with recent advances in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal: median survival after diagnosis is about 14 months. Established good prognostic factors are limited, but include young age, high Karnofsky Performance Status (KPS), high mini-mental status examination score, O6-methylguanine methyltransferase promoter methylation, and resection of > 98% of the tumor. Standard treatment includes resection, followed by concurrent chemotherapy and radiotherapy. GBM research is being conducted worldwide at a remarkable pace, with some of the more recent promising studies focused on identification of aberrant genetic events and signaling pathways, tumor stem cell identification and characterization, modulation of tumor immunological responses, combination therapies, and understanding of the rare long-term survivors. Past treatment strategies have failed for various reasons; however, newer strategies in trials today and on the horizon encourage optimism. To help illustrate 'where we have been' with this fatal disease and 'where we are going' with contemporary studies, we include in this review a detailed history of Phase III clinical trials for GBM, with a final emphasis on exciting new treatment strategies that offer hope for future GBM therapy.

Authors
Adamson, C; Kanu, OO; Mehta, AI; Di, C; Lin, N; Mattox, AK; Bigner, DD
MLA Citation
Adamson, C, Kanu, OO, Mehta, AI, Di, C, Lin, N, Mattox, AK, and Bigner, DD. "Glioblastoma multiforme: a review of where we have been and where we are going." Expert Opin Investig Drugs 18.8 (August 2009): 1061-1083. (Review)
PMID
19555299
Source
pubmed
Published In
Expert Opinion on Investigational Drugs
Volume
18
Issue
8
Publish Date
2009
Start Page
1061
End Page
1083
DOI
10.1517/13543780903052764

Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab.

INTRODUCTION: Carcinomatous meningitis (CM) is a devastating disease characterized by the dissemination of malignant tumor cells into the subarachnoid space along the brain and spine. Systemic treatment with monoclonal antibody (mAb) trastuzumab can be effective against HER2-positive systemic breast carcinoma but, like other therapies, is ineffective against CM. The goal of this study was to evaluate the therapeutic effect of alpha-particle emitting (211)At-labeled trastuzumab following intrathecal administration in a rat model of breast carcinoma CM. METHODS: Athymic rats were injected intrathecally with MCF-7/HER2-18 breast carcinoma cells through a surgically implanted indwelling intrathecal catheter. In Experiment 1, animals received 33 or 66 muCi (211)At-labeled trastuzumab, cold trastuzumab or saline. In Experiment 2, animals were inoculated with a lower tumor burden and received 46 or 92 muCi (211)At-labeled trastuzumab or saline. In Experiment 3, animals received 28 muCi (211)At-labeled trastuzumab, 30 muCi (211)At-labeled TPS3.2 control mAb or saline. Histopathological analysis of the neuroaxis was performed at the end of the study. RESULTS: In Experiment 1, median survival increased from 21 days for the saline and cold trastuzumab groups to 45 and 48 days for 33 and 66 muCi (211)At-labeled trastuzumab, respectively. In Experiment 2, median survival increased from 23 days for saline controls to 68 and 92 days for 46 and 92 muCi (211)At-labeled trastuzumab, respectively. In Experiment 3, median survival increased from 20 days to 29 and 36 days for animals treated with (211)At-labeled TPS3.2 and (211)At-labeled trastuzumab, respectively. Long-term survivors were observed exclusively in the (211)At-trastuzumab-treated groups. CONCLUSION: Intrathecal (211)At-labeled trastuzumab shows promise as a treatment for patients with HER2-positive breast CM.

Authors
Boskovitz, A; McLendon, RE; Okamura, T; Sampson, JH; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, McLendon, RE, Okamura, T, Sampson, JH, Bigner, DD, and Zalutsky, MR. "Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of alpha-particle-emitting (211)At-labeled trastuzumab." Nucl Med Biol 36.6 (August 2009): 659-669.
PMID
19647172
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
36
Issue
6
Publish Date
2009
Start Page
659
End Page
669
DOI
10.1016/j.nucmedbio.2009.04.003

Sample type bias in the analysis of cancer genomes.

There is widespread agreement that cancer gene discovery requires high-quality tumor samples. However, whether primary tumors or cultured samples are superior for cancer genomics has been a longstanding subject of debate. This debate has recently become more important because federally funded cancer genomics has been centralized under The Cancer Genome Atlas, which has chosen to focus exclusively on primary tumors. Here, we provide a data-driven "perspective" on the effect of sample type selection on cancer genomics research. We show that, in the case of glioblastoma multiforme, primary tumors and xenografts are best for the identification of amplifications, whereas xenografts and cell lines are superior for the identification of homozygous deletions. We also note that many of the most important oncogenes and tumor suppressor genes have been discovered through the use of cell lines and xenografts, and highlight the lack of published evidence supporting the dogma that ex vivo culture generates artifactual genetic lesions. Based on this analysis, we suggest that cancer genomics projects such as The Cancer Genome Atlas should include a variety of sample types such as xenografts and cell lines in their integrated genomic analysis of cancer.

Authors
Solomon, DA; Kim, J-S; Ressom, HW; Sibenaller, Z; Ryken, T; Jean, W; Bigner, D; Yan, H; Waldman, T
MLA Citation
Solomon, DA, Kim, J-S, Ressom, HW, Sibenaller, Z, Ryken, T, Jean, W, Bigner, D, Yan, H, and Waldman, T. "Sample type bias in the analysis of cancer genomes." Cancer Res 69.14 (July 15, 2009): 5630-5633.
PMID
19567670
Source
pubmed
Published In
Cancer Research
Volume
69
Issue
14
Publish Date
2009
Start Page
5630
End Page
5633
DOI
10.1158/0008-5472.CAN-09-1055

Tyrosine phosphorylation of the human glutathione S-transferase P1 by epidermal growth factor receptor.

Epidermal growth factor receptor (EGFR) gene amplification, mutations, and/or aberrant activation are frequent abnormalities in malignant gliomas and other human cancers and have been associated with an aggressive clinical course and a poor therapeutic outcome. Elevated glutathione S-transferase P1 (GSTP1), a major drug-metabolizing and stress response signaling protein, is also associated with drug resistance and poor clinical outcome in gliomas and other cancers. Here, we provide evidence that GSTP1 is a downstream EGFR target and that EGFR binds to and phosphorylates tyrosine residues in the GSTP1 protein in vitro and in vivo. Mass spectrometry and mutagenesis analyses in a cell-free system and in gliomas cells identified Tyr-7 and Tyr-198 as major EGFR-specific phospho-acceptor residues in the GSTP1 protein. The phosphorylation increased GSTP1 enzymatic activity significantly, and computer-based modeling showed a corresponding increase in electronegativity of the GSTP1 active site. In human glioma and breast cancer cells, epidermal growth factor stimulation rapidly increased GSTP1 tyrosine phosphorylation and decreased cisplatin sensitivity. Lapatinib, a clinically active EGFR inhibitor, significantly reversed the epidermal growth factor-induced cisplatin resistance. These data define phosphorylation and activation of GSTP1 by EGFR as a novel, heretofore unrecognized component of the EGFR signaling network and a novel mechanism of tumor drug resistance, particularly in tumors with elevated GSTP1 and/or activated EGFR.

Authors
Okamura, T; Singh, S; Buolamwini, J; Haystead, T; Friedman, H; Bigner, D; Ali-Osman, F
MLA Citation
Okamura, T, Singh, S, Buolamwini, J, Haystead, T, Friedman, H, Bigner, D, and Ali-Osman, F. "Tyrosine phosphorylation of the human glutathione S-transferase P1 by epidermal growth factor receptor." J Biol Chem 284.25 (June 19, 2009): 16979-16989.
PMID
19254954
Source
pubmed
Published In
The Journal of biological chemistry
Volume
284
Issue
25
Publish Date
2009
Start Page
16979
End Page
16989
DOI
10.1074/jbc.M808153200

Glioblastoma multiforme: a review of therapeutic targets.

Glioblastoma is the commonest primary brain tumor, as well as the deadliest. Malignant gliomas such as glioblastoma multiforme (GBM) present some of the greatest challenges in the management of cancer patients worldwide, despite notable recent achievements in oncology. Even with aggressive surgical resections using state-of-the-art preoperative and intraoperative neuroimaging, along with recent advances in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal: survival after diagnosis is about 1 year. Established prognostic factors are limited, but include age, Karnofsky performance status, mini-mental status examination score, O6-methylguanine methyltransferase promoter methylation and extent of surgery. Standard treatment includes resection of > 95% of the tumor, followed by concurrent chemotherapy and radiotherapy. Nevertheless, GBM research is being conducted worldwide at a remarkable pace, in the laboratory and at the bedside, with some of the more recent promising studies focused on identification of aberrant genetic events and signaling pathways to develop molecular-based targeted therapies, tumor stem cell identification and characterization, modulation of tumor immunological responses and understanding of the rare long-term survivors. With this universally fatal disease, any small breakthrough will have a significant impact on survival and provide hope to the thousands of patients who receive this diagnosis annually. This review describes the epidemiology, clinical presentation, pathology and tumor immunology, with a focus on understanding the molecular biology that underlies the current targeted therapeutics being tested.

Authors
Kanu, OO; Mehta, A; Di, C; Lin, N; Bortoff, K; Bigner, DD; Yan, H; Adamson, DC
MLA Citation
Kanu, OO, Mehta, A, Di, C, Lin, N, Bortoff, K, Bigner, DD, Yan, H, and Adamson, DC. "Glioblastoma multiforme: a review of therapeutic targets." Expert Opin Ther Targets 13.6 (June 2009): 701-718. (Review)
PMID
19409033
Source
pubmed
Published In
Expert Opinion on Therapeutic Targets
Volume
13
Issue
6
Publish Date
2009
Start Page
701
End Page
718
DOI
10.1517/14728220902942348

Bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea activates the ATR-Chk1 pathway independently of the mismatch repair pathway.

The presence of DNA damage initiates signaling through the ataxia-telangiectasia mutated kinase (ATM) and the ATM- and the Rad3-related kinase (ATR), which phosphorylate, thus activating, the checkpoint kinases (Chk) 1 and 2, which leads to cell cycle arrest. The bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) is cytotoxic primarily by inducing DNA monoadducts and ultimately, interstrand cross-links, which block DNA replication. In this study, we investigated the activation of the ATR-Chk1 pathway in response to BCNU treatment and the dependence of this response on the DNA mismatch repair (MMR) capacity. Medulloblastoma cells were exposed to low and moderate doses of BCNU, and the effects on this DNA damage signaling pathway were examined. In response to BCNU, Chk1 was found to be phosphorylated at serine 345 and exhibited increased kinase activity. Caffeine and wortmannin, which are broad-spectrum inhibitors of ATM and ATR, reduced this phosphorylation. Cell cycle analysis further revealed an accumulation of cells in the S phase in response to BCNU, an effect that was attenuated by caffeine. Small interfering RNA knockdown of ATR also reduced Chk1 phosphorylation after exposure to BCNU. However, knockdown of ATM had no effect on the observed Chk1 phosphorylation, suggesting that ATR was primarily responsible for Chk1 activation. Analysis of Chk1 activation in cells deficient in MMR proteins MutLalpha or MutSalpha indicated that the DNA damage response induced by BCNU was independent of the MMR apparatus. This MMR-independent activation seems to be the result of DNA interstrand cross-link formation.

Authors
Cui, B; Johnson, SP; Bullock, N; Ali-Osman, F; Bigner, DD; Friedman, HS
MLA Citation
Cui, B, Johnson, SP, Bullock, N, Ali-Osman, F, Bigner, DD, and Friedman, HS. "Bifunctional DNA alkylator 1,3-bis(2-chloroethyl)-1-nitrosourea activates the ATR-Chk1 pathway independently of the mismatch repair pathway." Mol Pharmacol 75.6 (June 2009): 1356-1363.
PMID
19261750
Source
pubmed
Published In
Molecular pharmacology
Volume
75
Issue
6
Publish Date
2009
Start Page
1356
End Page
1363
DOI
10.1124/mol.108.053124

Effect of daclizumab on T-Reg counts and EGFRvIII-specific immune responses in GBM

Authors
Sampson, JH; Archer, GE; Bigner, DD; Schmittling, RJ; II, HJE; Davis, T; Friedman, HS; Keler, T; Reardon, DA; Mitchell, DA
MLA Citation
Sampson, JH, Archer, GE, Bigner, DD, Schmittling, RJ, II, HJE, Davis, T, Friedman, HS, Keler, T, Reardon, DA, and Mitchell, DA. "Effect of daclizumab on T-Reg counts and EGFRvIII-specific immune responses in GBM." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Epidermal growth factor receptor variant III (EGFRvIII) vaccine ( CDX-110) in GBM

Authors
Heimberger, AB; Archer, GE; Mitchell, DA; Bigner, DD; Schmittling, RJ; II, HJE; Davis, T; Friedman, HS; Keler, T; Reardon, DA; Sampson, JH
MLA Citation
Heimberger, AB, Archer, GE, Mitchell, DA, Bigner, DD, Schmittling, RJ, II, HJE, Davis, T, Friedman, HS, Keler, T, Reardon, DA, and Sampson, JH. "Epidermal growth factor receptor variant III (EGFRvIII) vaccine ( CDX-110) in GBM." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Temozolomide (TMZ) and bevacizumab (BV) as initial treatment for unresectable or multifocal glioblastoma multiforme (GBM)

Authors
Peters, K; Desjardins, A; Reardon, DA; Perry, S; II, HJE; Bailey, L; Friedman, AH; Friedman, HS; Bigner, DD; Vredenburgh, JJ
MLA Citation
Peters, K, Desjardins, A, Reardon, DA, Perry, S, II, HJE, Bailey, L, Friedman, AH, Friedman, HS, Bigner, DD, and Vredenburgh, JJ. "Temozolomide (TMZ) and bevacizumab (BV) as initial treatment for unresectable or multifocal glioblastoma multiforme (GBM)." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Phase I trial of vendetanib and oral etoposide for recurrent malignant gliomas

Authors
II, HJ; Vredenburgh, J; Reardon, D; Desjardins, A; Peters, K; Gururangan, S; Norfleet, J; Friedman, A; Bigner, D; Friedman, HS
MLA Citation
II, HJ, Vredenburgh, J, Reardon, D, Desjardins, A, Peters, K, Gururangan, S, Norfleet, J, Friedman, A, Bigner, D, and Friedman, HS. "Phase I trial of vendetanib and oral etoposide for recurrent malignant gliomas." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Identification of microbial DNA in human cancer.

Microorganisms have been associated with many types of human diseases; however, a significant number of clinically important microbial pathogens remain to be discovered.We have developed a genome-wide approach, called Digital Karyotyping Microbe Identification (DK-MICROBE), to identify genomic DNA of bacteria and viruses in human disease tissues. This method involves the generation of an experimental DNA tag library through Digital Karyotyping (DK) followed by analysis of the tag sequences for the presence of microbial DNA content using a compiled microbial DNA virtual tag library.To validate this technology and to identify pathogens that may be associated with human cancer pathogenesis, we used DK-MICROBE to determine the presence of microbial DNA in 58 human tumor samples, including brain, ovarian, and colorectal cancers. We detected DNA from Human herpesvirus 6 (HHV-6) in a DK library of a colorectal cancer liver metastasis and in normal tissue from the same patient.DK-MICROBE can identify previously unknown infectious agents in human tumors, and is now available for further applications for the identification of pathogen DNA in human cancer and other diseases.

Authors
Duncan, CG; Leary, RJ; Lin, JC-H; Cummins, J; Di, C; Schaefer, CF; Wang, T-L; Riggins, GJ; Edwards, J; Bigner, D; Kopelovich, L; Vogelstein, B; Kinzler, KW; Velculescu, VE; Yan, H
MLA Citation
Duncan, CG, Leary, RJ, Lin, JC-H, Cummins, J, Di, C, Schaefer, CF, Wang, T-L, Riggins, GJ, Edwards, J, Bigner, D, Kopelovich, L, Vogelstein, B, Kinzler, KW, Velculescu, VE, and Yan, H. "Identification of microbial DNA in human cancer." BMC medical genomics 2 (May 8, 2009): 22-.
PMID
19426505
Source
epmc
Published In
BMC Medical Genomics
Volume
2
Publish Date
2009
Start Page
22
DOI
10.1186/1755-8794-2-22

Podoplanin is a novel antibody-based therapeutic target for glioblastoma

Authors
Kato, Y; Mishima, K; Kaneko, M; Zalutsky, M; Kuan, C-T; Bigner, D
MLA Citation
Kato, Y, Mishima, K, Kaneko, M, Zalutsky, M, Kuan, C-T, and Bigner, D. "Podoplanin is a novel antibody-based therapeutic target for glioblastoma." CANCER RESEARCH 69 (May 1, 2009).
Source
wos-lite
Published In
Cancer Research
Volume
69
Publish Date
2009

Effect of daclizumab on TReg counts and EGFRvIII-specific immune responses in GBM.

2034 Background: TRegs are increased in patients with GBM and constitutively express the high affinity interleukin-2 receptor (IL-2Rα). Treatment with an antibody that blocks IL-2Rα signaling functionally inactivates and eliminates TRegs without inducing autoimmune toxicity in murine models. We hypothesized that daclizumab, a commercially-available, IL-2Rα-specific antibody would function identically.A randomized phase II clinical trial assessed the effects of daclizumab in the context of the cancer vaccine, CDX-110, which is comprised of an EGFRvIII-specific peptide sequence linked to KLH. EGFRvIII is a constitutively activated and immunogenic mutation not expressed in normal tissues, but widely expressed in GBMs and other neoplasms. In patients with newly-diagnosed, EGFRvIII+ GBM, after resection and radiation/TMZ, patients received CDX-110 vaccinations biweekly x 3, then monthly until tumor progression in combination with TMZ (200 mg/m2 x 5/28 days). Half the patients were randomized to receive daclizumab (1mg/Kg x1) at the first vaccine. The others received saline in a double-blinded fashion.There were no drug related SAEs. EGFRvIII-specific immune responses were generated in all patients, and all immune responses were sustained or enhanced during subsequent TMZ cycles. Preliminary analysis (n = 4) suggests that daclizumab reduces Treg (CD4+CD25+CD45RO+FOXP3+) numbers [change 82.4 ± 7.1% from baseline (p = 0.011; t-test)] without reducing overall CD8+ or CD4+ T-cell counts. Tregs decreased only 3.7 + 11.0% after vaccination in the saline treated group during the same interval. Preliminary analysis (n = 4) also suggest that daclizumab enhanced EGFRvIII-specific immune responses (p = 0.01; t-test) and enhanced the titer of cytotoxic EGFRvIII-specific IgG1 isotype antibodies compared to the saline treated group (p = 0.003; t-test) and compared to previously vaccinated patients who did not receive daclizumab (p = 0.0015; t-test). TTP and OS survival in both arms has not been reached.Daclizumab may reduce Treg counts in patients with GBM. TMZ and daclizumab may enhance EGFRvIII-targeted immune responses despite lymphodepletion. These combinations are currently under further investigation. [Table: see text].

Authors
Sampson, JH; Archer, GE; Bigner, DD; Schmittling, RJ; Herndon, JE; Davis, T; Friedman, HS; Keler, T; Reardon, DA; Mitchell, DA
MLA Citation
Sampson, JH, Archer, GE, Bigner, DD, Schmittling, RJ, Herndon, JE, Davis, T, Friedman, HS, Keler, T, Reardon, DA, and Mitchell, DA. "Effect of daclizumab on TReg counts and EGFRvIII-specific immune responses in GBM." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 2034-.
PMID
27964629
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
2034

Epidermal growth factor receptor variant III (EGFRvIII) vaccine (CDX-110) in GBM.

2021 Background: Unlike conventional therapies for GBM, immunologic targeting of tumor-specific gene mutations allows precise eradication of neoplastic cells with reduced toxicity. EGFRvIII is a constitutively activated and immunogenic mutation not expressed in normal tissues, but widely expressed in GBM and other neoplasms. The cancer vaccine CDX-110 is comprised of an EGFRvIII-specific peptide sequence linked to keyhole limpet hemocyanin (KLH).A phase II multi-center trial assessed the immunogenicity and efficacy of CDX-110 in patients with newly-diagnosed, EGFRvIII+ GBM. After resection and radiation / TMZ, patients received CDX-110 vaccinations biweekly x 3, then monthly until tumor progression. Sequential cohorts received CDX-110 alone [ACTIVATE (n = 18)] or in combination with TMZ (200 mg/m2 x 5/28 days [ACT II A (n = 13)]) or (100 mg/m2 x 21/28 days [ACT II B (n=10)]).Reversible systemic drug hypersensitivity reactions were seen in 1 ACTIVATE and 4 ACT II patients. Two patients had non-specific changes on MRI which were possibly due to the vaccine but which resolved. Despite grade 2 or 3 lymphopenia in all ACT II patients, EGFRvIII-specific immune responses were generated in all patients, and all immune responses were sustained or enhanced during subsequent TMZ cycles. Although ACT II B patients had more severe TMZ-induced lymphopenia, they developed greater EGFRvIII-specific immune responses (p = 0.028) when compared to ACT II A. EGFRvIII-specific IgG1 also increased in avidity with vaccination (Ka>>2x109M-1) in a randomly selected subset of 4 patients (p = 0.000068). Of the 23 recurrent tumors studied, 18 lost EGFRvIII expression (p = 0.001). There are no significant differences between ACT II A and B in estimated median TTP (18.5 vs. 14.9 months, p = 0.31) and OS (23.6 vs. 19.9 months, p = 0.75). ACTIVATE TTP (14.2 months) and OS (26.0 months) and ACT II TTP (15.2 months) and OS (23.6 months) compare favorably to a TMZ-treated, matched historical control group (TTP: 6.3 months; OS: 15.0 months).CDX-110 vaccination in patients with GBM appears very promising. TMZ enhances immune responses despite lymphodepletion. CDX-110 with simultaneous TMZ is under further investigation in a larger phase II trial. [Table: see text].

Authors
Heimberger, AB; Archer, GE; Mitchell, DA; Bigner, DD; Schmittling, RJ; Herndon, JE; Davis, T; Friedman, HS; Keler, T; Reardon, DA; Sampson, JH
MLA Citation
Heimberger, AB, Archer, GE, Mitchell, DA, Bigner, DD, Schmittling, RJ, Herndon, JE, Davis, T, Friedman, HS, Keler, T, Reardon, DA, and Sampson, JH. "Epidermal growth factor receptor variant III (EGFRvIII) vaccine (CDX-110) in GBM." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 2021-.
PMID
27964605
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
2021

Phase I trial of vendetanib and oral etoposide for recurrent malignant gliomas.

e13016 Background: Recurrent malignant gliomas have a poor prognosis, with a median survival of 6-15 months, with grade 4 glioblastomas more aggressive than grade 3 anaplastic astrocytomas or oligodendrogliomas. Vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are critically important in glioma biology. Vandetanib is a multi-kinase inhibitor, predominantly of VEGF and EGF. We report a phase I trial of vandetanib in combination with oral etoposide for recurrent malignant glioma.Patients with histologically documented recurrent grade 3 or grade 4 malignant glioma were eligible. Patients were treated with daily oral vandetanib and oral etoposide. The trial design was a modified 3 + 3 Phase I design, with the dose levels outlined below.Eighteen patients have been accrued. There was more hematologic toxicity than expected, with 3/6 of the patients enrolled at dose level 1 developing grade 4 neutropenia. There were no DLT's at the -1 dose level. The protocol was amended to decrease the dose of etoposide to 50 mg daily for 21 days, then 7 days off and dose escalation of vandetanib started again at 100 mg daily. Six patients had no dose limiting toxicity at the new dose level 1 of vandetanib 100 mg daily and etoposide 50 mg daily. Dose escalation continues. There has been clinical activity, with patients remaining stable on study for multiple cycles.Vandetanib and oral etoposide appear to interact to produce more marrow toxicity than expected. A phase II trial is planned when the MTD of vandetanib with reduced dose etoposide is determined. [Table: see text] No significant financial relationships to disclose.

Authors
Herndon, J; Vredenburgh, J; Reardon, D; Desjardins, A; Peters, K; Gururangan, S; Norfleet, J; Friedman, A; Bigner, D; Friedman, HS
MLA Citation
Herndon, J, Vredenburgh, J, Reardon, D, Desjardins, A, Peters, K, Gururangan, S, Norfleet, J, Friedman, A, Bigner, D, and Friedman, HS. "Phase I trial of vendetanib and oral etoposide for recurrent malignant gliomas." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): e13016-.
PMID
27962830
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
e13016

Temozolomide (TMZ) and bevacizumab (BV) as initial treatment for unresectable or multifocal glioblastoma multiforme (GBM).

e13025 Background: GBMs are vascular tumors and inherently resistant to therapy. The prognosis for patients is poor with a median survival of 9-15 months. Patients with unresectable or multifocal GBMs have an even poorer prognosis, with a median survival of 6-8 months. Given the angiogenic phenotype of GBM, we conducted a phase II trial of upfront BV and 5-day TMZ in newly diagnosed unresectable or multifocal GBMs.Patients had histologically documented newly diagnosed GBMs that were unresectable or multifocal. Patients received up to 4 cycles of temozolomide at 200 mg/m2/d days 1-5 and BV at 10 mg/kg on days 1 and 14 in a 28 day cycle. An MRI was performed after every cycle and patients continued on therapy as long as there was no tumor progression, grade 4 non-hematologic toxicity or recurrent grade 4 hematologic toxicity after a dose reduction to 150 mg/m2/d. The primary endpoint was tumor response using the modified MacDonald criteria plus FLAIR and T2 sequences to evaluate non-enhancing tumor. Results were evaluated by two independent reviewers.41 patients were enrolled between October 2007 and September 2008 and 31 patients were analyzed after completion of cycle 2. As the best response, there were 8 (25.8%) partial responses, 19 (61.3 %) patients with stable disease, and 4(12.9 %) had disease progression. 19 of the 41 patients enrolled completed four cycles without tumor progression. The regimen was tolerable, with 3 grade 4 hematologic toxicities including neutropenia and thrombocytopenia. There were 2 grade 4 non-hematologic toxicities, including pulmonary embolism. There were two CNS hemorrhages. The median PFS was 3.6 months (2.9 months, 4.4 months) and the median OS was 4.5 months (3.7 months, 5.3 months).Upfront temozolomide and bevacizumab was well tolerated, but synergistic chemotherapy or growth factor inhibitors need to be added to produce meaningful clinical benefit, particularly for unresectable or multifocal GBM. No significant financial relationships to disclose.

Authors
Peters, K; Desjardins, A; Reardon, DA; Perry, S; Herndon, JE; Bailey, L; Friedman, AH; Friedman, HS; Bigner, DD; Vredenburgh, JJ
MLA Citation
Peters, K, Desjardins, A, Reardon, DA, Perry, S, Herndon, JE, Bailey, L, Friedman, AH, Friedman, HS, Bigner, DD, and Vredenburgh, JJ. "Temozolomide (TMZ) and bevacizumab (BV) as initial treatment for unresectable or multifocal glioblastoma multiforme (GBM)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): e13025-.
PMID
27962792
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
e13025

Proteomic and immunologic analyses of brain tumor exosomes.

Brain tumors are horrific diseases with almost universally fatal outcomes; new therapeutics are desperately needed and will come from improved understandings of glioma biology. Exosomes are endosomally derived 30-100 nm membranous vesicles released from many cell types into the extracellular milieu; surprisingly, exosomes are virtually unstudied in neuro-oncology. These microvesicles were used as vaccines in other tumor settings, but their immunological significance is unevaluated in brain tumors. Our purpose here is to report the initial biochemical, proteomic, and immunological studies on murine brain tumor exosomes, following known procedures to isolate exosomes. Our findings show that these vesicles have biophysical characteristics and proteomic profiles similar to exosomes from other cell types but that brain tumor exosomes have unique features (e.g., very basic isoelectric points, expressing the mutated tumor antigen EGFRvIII and the putatively immunosuppressive cytokine TGF-beta). Administration of such exosomes into syngeneic animals produced both humoral and cellular immune responses in immunized hosts capable of rejecting subsequent tumor challenges but failed to prolong survival in established orthotopic models. Control animals received saline or cell lysate vaccines and showed no antitumor responses. Exosomes and microvesicles isolated from sera of patients with brain tumors also possess EGFR, EGFRvIII, and TGF-beta. We conclude that exosomes released from brain tumor cells are biochemically/biophysically like other exosomes and have immune-modulating properties. They can escape the blood-brain barrier, with potential systemic and distal signaling and immune consequences.

Authors
Graner, MW; Alzate, O; Dechkovskaia, AM; Keene, JD; Sampson, JH; Mitchell, DA; Bigner, DD
MLA Citation
Graner, MW, Alzate, O, Dechkovskaia, AM, Keene, JD, Sampson, JH, Mitchell, DA, and Bigner, DD. "Proteomic and immunologic analyses of brain tumor exosomes." FASEB J 23.5 (May 2009): 1541-1557.
PMID
19109410
Source
pubmed
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
23
Issue
5
Publish Date
2009
Start Page
1541
End Page
1557
DOI
10.1096/fj.08-122184

RNA Transfected Dendritic Cell Vaccines Targeting Human Cytomegalovirus Antigens in Patients with Glioblastoma

Authors
Mitchell, DA; Archer, GE; Bigner, DD; Friedman, HS; Lally-Goss, D; Perry, B; II, HJE; McGehee, S; McLendon, RE; Reardon, D; Sampson, JH
MLA Citation
Mitchell, DA, Archer, GE, Bigner, DD, Friedman, HS, Lally-Goss, D, Perry, B, II, HJE, McGehee, S, McLendon, RE, Reardon, D, and Sampson, JH. "RNA Transfected Dendritic Cell Vaccines Targeting Human Cytomegalovirus Antigens in Patients with Glioblastoma." May 2009.
Source
wos-lite
Published In
Molecular Therapy
Volume
17
Publish Date
2009
Start Page
S93
End Page
S93

Glioblastoma Multiforme Oncogenomics and Signaling Pathways.

In the adult population, glioblastoma multiforme is one of the most common primary brain tumors encountered. Unfortunately, this highly malignant tumor represents over 50% of all types of primary central nervous system gliomas. The vast majority of GBMs develops quite rapidly without clinical, radiological, or morphologic evidence of a less malignant precursor lesion (primary or de novo GBMs), as compared to secondary GBMs that develop slowly by progression from diffuse low-grade astrocytomas. These GBM subtypes must be kept in mind because they may constitute distinct disease entities. Even though they look histologically quite similar, they likely involve different genetic alterations and signaling pathways. Decades of surgical therapy, radiotherapy, and chemotherapy have failed to drastically change survival. Clearly, we do not fully understand this tumor; however, the exciting genetic revolution in glioma research over the past decade is providing a promising outlook for exploring this tumor at the genetic level. Science has begun to elucidate the numerous genetic alterations and critical signaling pathways, and it has opened new exciting areas of research such as glioma stem cell biology and neoangiogenesis. This work has already begun to improve our understanding of GBM cell proliferation, migration, and invasion. Indeed, exciting novel targeted therapies are making their way to clinical trials based on this increased knowledge. This review provides the current understanding of GBM oncogenomics, signaling pathways, and glioma stem cell biology and discusses the potential new therapeutic targets on the horizon.

Authors
Kanu, OO; Hughes, B; Di, C; Lin, N; Fu, J; Bigner, DD; Yan, H; Adamson, C
MLA Citation
Kanu, OO, Hughes, B, Di, C, Lin, N, Fu, J, Bigner, DD, Yan, H, and Adamson, C. "Glioblastoma Multiforme Oncogenomics and Signaling Pathways." Clin Med Oncol 3 (April 8, 2009): 39-52.
PMID
19777070
Source
pubmed
Published In
Clin Med Oncol
Volume
3
Publish Date
2009
Start Page
39
End Page
52

DUAL-SPECIFIC IMMUNOTOXIN, D2C7 (SCDSFV)-PE38KDEL, FOR BRAIN TUMOR TREATMENT

Authors
Chandramohan, V; Kuan, C-T; Pegram, CN; Pastan, I; Bigner, DD
MLA Citation
Chandramohan, V, Kuan, C-T, Pegram, CN, Pastan, I, and Bigner, DD. "DUAL-SPECIFIC IMMUNOTOXIN, D2C7 (SCDSFV)-PE38KDEL, FOR BRAIN TUMOR TREATMENT." NEURO-ONCOLOGY 11.2 (April 2009): 223-223.
Source
wos-lite
Published In
Neuro-Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
223
End Page
223

Association between glioma and history of allergies, asthma, and eczema: a case-control study with three groups of controls.

Because glioma etiology is largely unknown, the inverse association of glioma risk with atopic conditions is promising and deserves close scrutiny. We examined the association between a history of allergies, asthma, and eczema, and glioma risk using sibling, friend, and clinic-based controls. This analysis included 388 incident glioma cases and 80 sibling, 191 friend, and 177 clinic-based controls. Each subject's medical history was assessed via a Web-based or telephone survey. Odds ratios (OR) and their 95% confidence intervals (CI) for the associations with allergies, asthma, eczema, and the overall number of these conditions were calculated from conditional (for sibling and friend controls) and unconditional (for clinic-based controls) logistic models. Allergies were consistently inversely associated with the glioma: ORs were 0.53 (95% CI, 0.15-1.84), 0.54 (95% CI, 0.28-1.07), and 0.34 (95% CI, 0.23-0.50) with sibling, friend, and clinic-based controls, respectively. Asthma showed an inverse association only in the comparison with sibling controls (OR, 0.43; 95% CI, 0.19-1.00). Eczema showed an inverse association only in the comparison with friend controls (OR, 0.42; 95% CI, 0.15-1.18). The overall number of these conditions (ordinal score 0, 1, 2, 3) was inversely associated with glioma: The risk decreased 31% to 45% with each addition of an atopic condition. These estimates were the most stable when different control groups were considered. Comparing the prevalence of these conditions in the three control groups with published data, we note that clinic-based controls generally better approximate the prevalence data for population-based groups. These controls seem to present a reasonable choice for clinic-centered case-control studies.

Authors
Il'yasova, D; McCarthy, B; Marcello, J; Schildkraut, JM; Moorman, PG; Krishnamachari, B; Ali-Osman, F; Bigner, DD; Davis, F
MLA Citation
Il'yasova, D, McCarthy, B, Marcello, J, Schildkraut, JM, Moorman, PG, Krishnamachari, B, Ali-Osman, F, Bigner, DD, and Davis, F. "Association between glioma and history of allergies, asthma, and eczema: a case-control study with three groups of controls." Cancer Epidemiol Biomarkers Prev 18.4 (April 2009): 1232-1238.
PMID
19336556
Source
pubmed
Published In
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
Volume
18
Issue
4
Publish Date
2009
Start Page
1232
End Page
1238
DOI
10.1158/1055-9965.EPI-08-0995

INDUCTION OF IMMUNOLOGIC AND CLINICAL RESPONSES WITH EGFRVIII-TARGETED VACCINE (CDX-110) WITH CYCLES OF TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED EGFRVIII-POSITIVE GBM

Authors
Archer, GE; Heimberger, AB; Bigner, DD; Davis, T; Friedman, HS; Keler, T; McLendon, RE; Mitchell, DA; Reardon, D; Sawaya, R; Vredenberg, J; Sampson, JH
MLA Citation
Archer, GE, Heimberger, AB, Bigner, DD, Davis, T, Friedman, HS, Keler, T, McLendon, RE, Mitchell, DA, Reardon, D, Sawaya, R, Vredenberg, J, and Sampson, JH. "INDUCTION OF IMMUNOLOGIC AND CLINICAL RESPONSES WITH EGFRVIII-TARGETED VACCINE (CDX-110) WITH CYCLES OF TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED EGFRVIII-POSITIVE GBM." NEURO-ONCOLOGY 11.2 (April 2009): 224-224.
Source
wos-lite
Published In
Neuro-Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
224
End Page
224

RECOMBINANT ANTIBODY-BASED MOLECULAR THERAPEUTICS FOR BRAIN TUMOR IMMUNOTHERAPY

Authors
Kuan, C-T; Wakiya, K; II, HJE; Wikstrand, CJ; McLendon, RE; Zalutsky, MR; Pastan, IH; Bigner, DD
MLA Citation
Kuan, C-T, Wakiya, K, II, HJE, Wikstrand, CJ, McLendon, RE, Zalutsky, MR, Pastan, IH, and Bigner, DD. "RECOMBINANT ANTIBODY-BASED MOLECULAR THERAPEUTICS FOR BRAIN TUMOR IMMUNOTHERAPY." NEURO-ONCOLOGY 11.2 (April 2009): 224-224.
Source
wos-lite
Published In
Neuro-Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
224
End Page
224

OTX2 IS ONCOGENIC AND PREDICTS DECREASED SURVIVAL IN MEDULLOBLASTOMA PATIENTS

Authors
Guruiangan, S; Yan, H; Adamson, C; Shi, Q; McLendon, R; Bigner, D
MLA Citation
Guruiangan, S, Yan, H, Adamson, C, Shi, Q, McLendon, R, and Bigner, D. "OTX2 IS ONCOGENIC AND PREDICTS DECREASED SURVIVAL IN MEDULLOBLASTOMA PATIENTS." NEURO-ONCOLOGY 11.2 (April 2009): 234-234.
Source
wos-lite
Published In
Neuro-Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
234
End Page
234

EGF RECEPTOR TYROSINE KINASE MEDIATES A NOVEL PATHWAY OF DRUG RESISTANCE IN MALIGNANT GLIOMAS VIA TYROSINE PHOSPHORYLATION AND FUNCTIONAL ACTIVATION OF GLUTATHIONE S-TRANSFERASE P1

Authors
Okamura, T; Singh, S; Buolamwini, JK; Friedman, HS; Bigner, DD; Ali-Osman, F
MLA Citation
Okamura, T, Singh, S, Buolamwini, JK, Friedman, HS, Bigner, DD, and Ali-Osman, F. "EGF RECEPTOR TYROSINE KINASE MEDIATES A NOVEL PATHWAY OF DRUG RESISTANCE IN MALIGNANT GLIOMAS VIA TYROSINE PHOSPHORYLATION AND FUNCTIONAL ACTIVATION OF GLUTATHIONE S-TRANSFERASE P1." NEURO-ONCOLOGY 11.2 (April 2009): 218-218.
Source
wos-lite
Published In
Neuro-Oncology
Volume
11
Issue
2
Publish Date
2009
Start Page
218
End Page
218

Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma.

PURPOSE: This phase II trial was designed to define the role of O(6)-benzylguanine (O(6)-BG) in restoring temozolomide sensitivity in patients with recurrent or progressive, temozolomide-resistant malignant glioma and to evaluate the safety of administering O(6)-BG in combination with temozolomide. PATIENTS AND METHODS: Patients were accrued into two independent strata on the basis of histology: glioblastoma multiforme (GBM) and anaplastic glioma. Both temozolomide and O(6)-BG were administered on day 1 of a 28-day treatment cycle. Patients were administered a 1-hour O(6)-BG infusion at a dose of 120 mg/m(2) followed immediately by a 48-hour infusion at a dose of 30 mg/m(2)/d. Temozolomide was administered orally within 60 minutes of the end of the 1-hour O(6)-BG infusion at a dose of 472 mg/m(2). The primary end point was objective response rate. Secondary end points included progression-free survival, overall survival, and safety. RESULTS: Sixty-six of 67 patients who enrolled were treated with temozolomide and O(6)-BG. One of 34 patients (3%) with GBM (95% CI, 0.1% to 15%) and five of 32 assessable patients (16%) with anaplastic glioma (95% CI, 5% to 33%) were responders. The most commonly reported adverse events were grade 4 hematologic events experienced in 48% of the patients. CONCLUSION: O(6)-BG when added to a 1-day dosing regimen of temozolomide was able to restore temozolomide sensitivity in patients with temozolomide-resistant anaplastic glioma, but there seemed to be no significant restoration of temozolomide sensitivity in patients with temozolomide-resistant GBM.

Authors
Quinn, JA; Jiang, SX; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Walker, A; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Rich, JN, Gururangan, S, Friedman, AH, Bigner, DD, Sampson, JH, McLendon, RE, Herndon, JE, Walker, A, and Friedman, HS. "Phase II trial of temozolomide plus o6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma." J Clin Oncol 27.8 (March 10, 2009): 1262-1267.
PMID
19204199
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
27
Issue
8
Publish Date
2009
Start Page
1262
End Page
1267
DOI
10.1200/JCO.2008.18.8417

BCNU-sequestration by metallothioneins may contribute to resistance in a medulloblastoma cell line.

PURPOSE: Resistance of neoplastic cells to the alkylating drug BCNU [1,3-bis(2-chloroethyl)-1-nitrosourea] has been correlated with expression of O (6)-methylguanine-DNA methyltransferase, which repairs the O (6)-chloroethylguanine produced by the drug. Other possible mechanisms of resistance include raised levels of glutathione or increased repair of the DNA interstrand cross-links formed by BCNU. Transcriptional profiling revealed the upregulation of several metallothionein (MT) genes in a BCNU-resistant medulloblastoma cell line [D341 MED (OBR)] relative to its parental line. Previous studies have shown that MTs, through their reactive thiol groups can quench nitrogen mustard-derived alkylating drugs. In this report, we evaluate whether MTs can also quench BCNU. METHODS: To demonstrate the binding of BCNU to MT, we used an assay that measured the release of the MT-bound divalent cations (Zn(2+), Cd(2+)) upon their displacement by the drug. We also measured the decomposition rates of BCNU at those reaction conditions. RESULTS: The rate of release of the cations was higher in pH 7.4 than at pH 7.0, which is likely a result of more rapid decomposition of BCNU (thus faster release of MT-binding intermediate) at pH 7.4 than at pH 7.0. CONCLUSION: We demonstrate that resistance to BCNU may be a result of elevated levels of MTs which act by sequestering the drug's decomposition product(s).

Authors
Bacolod, MD; Fehdrau, R; Johnson, SP; Bullock, NS; Bigner, DD; Colvin, M; Friedman, HS
MLA Citation
Bacolod, MD, Fehdrau, R, Johnson, SP, Bullock, NS, Bigner, DD, Colvin, M, and Friedman, HS. "BCNU-sequestration by metallothioneins may contribute to resistance in a medulloblastoma cell line." Cancer Chemother Pharmacol 63.4 (March 2009): 753-758.
PMID
18633619
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
63
Issue
4
Publish Date
2009
Start Page
753
End Page
758
DOI
10.1007/s00280-008-0792-9

Human exposure to selected animal neurocarcinogens: a biomarker-based assessment and implications for brain tumor epidemiology.

This review is based on the proceedings from the Second Lebow Conference, held in Chicago in 2007. The conference concentrated on developing a framework for innovative studies in the epidemiology of environmental exposures, focusing specifically on the potential relationship with brain tumors. Researchers with different perspectives, including toxicology, pharmacokinetics, and epidemiological exposure assessment, exchanged information and ideas on the use of biomarkers of exposure in molecular epidemiology studies and summarized the current knowledge on methods and approaches for biomarker-based exposure assessment. This report presents the state of science regarding biomarker-based exposure assessment of the four most common neurocarcinogens: acrylamide, 1,3-butadiene, N-nitroso compounds, and polycyclic aromatic hydrocarbons. Importantly, these chemicals are also carcinogenic in other organs; therefore, this discussion is useful for environmental epidemiologists studying all cancer types.

Authors
Il'yasova, D; McCarthy, BJ; Erdal, S; Shimek, J; Goldstein, J; Doerge, DR; Myers, SR; Vineis, P; Wishnok, JS; Swenberg, JA; Bigner, DD; Davis, FG
MLA Citation
Il'yasova, D, McCarthy, BJ, Erdal, S, Shimek, J, Goldstein, J, Doerge, DR, Myers, SR, Vineis, P, Wishnok, JS, Swenberg, JA, Bigner, DD, and Davis, FG. "Human exposure to selected animal neurocarcinogens: a biomarker-based assessment and implications for brain tumor epidemiology." J Toxicol Environ Health B Crit Rev 12.3 (March 2009): 175-187. (Review)
PMID
19466671
Source
pubmed
Published In
Journal of Toxicology and Environmental Health Part B: Critical Reviews
Volume
12
Issue
3
Publish Date
2009
Start Page
175
End Page
187
DOI
10.1080/10937400902894152

IDH1 and IDH2 mutations in gliomas.

BACKGROUND: A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). METHODS: We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. RESULTS: We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and clinical characteristics, and patients with such tumors had a better outcome than those with wild-type IDH genes. Each of four tested IDH1 and IDH2 mutations reduced the enzymatic activity of the encoded protein. CONCLUSIONS: Mutations of NADP(+)-dependent isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority of several types of malignant gliomas.

Authors
Yan, H; Parsons, DW; Jin, G; McLendon, R; Rasheed, BA; Yuan, W; Kos, I; Batinic-Haberle, I; Jones, S; Riggins, GJ; Friedman, H; Friedman, A; Reardon, D; Herndon, J; Kinzler, KW; Velculescu, VE; Vogelstein, B; Bigner, DD
MLA Citation
Yan, H, Parsons, DW, Jin, G, McLendon, R, Rasheed, BA, Yuan, W, Kos, I, Batinic-Haberle, I, Jones, S, Riggins, GJ, Friedman, H, Friedman, A, Reardon, D, Herndon, J, Kinzler, KW, Velculescu, VE, Vogelstein, B, and Bigner, DD. "IDH1 and IDH2 mutations in gliomas." N Engl J Med 360.8 (February 19, 2009): 765-773.
PMID
19228619
Source
pubmed
Published In
The New England journal of medicine
Volume
360
Issue
8
Publish Date
2009
Start Page
765
End Page
773
DOI
10.1056/NEJMoa0808710

Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme.

PURPOSE: This phase II trial was designed to define the efficacy of Gliadel wafers in combination with an infusion of O6-benzylguanine (O6-BG) that suppresses tumor O6-alkylguanine-DNA alkyltransferase (AGT) levels in patients with recurrent glioblastoma multiforme for 5 days and to evaluate the safety of this combination therapy. EXPERIMENTAL DESIGN: This was a phase II, open-label, single center trial. On gross total resection of the tumor, up to eight Gliadel wafers were implanted. Bolus infusion of O6-BG was administered at 120 mg/m2 over 1 hour on days 1, 3, and 5, along with a continuous infusion at 30 mg/m2/d. The primary end points were 6-month overall survival (OS) and safety, and the secondary end points were 1-year, 2-year, and median OS. RESULTS: Fifty-two patients were accrued. The 6-month OS was 82% [95% confidence interval (95% CI), 72-93%]. The 1- and 2-year OS rates were 47% (95% CI, 35-63%) and 10% (95% CI, 3-32%), respectively. The median OS was 50.3 weeks (95% CI, 36.1-69.4 weeks). Treatment-related toxicity with this drug combination included grade 3 hydrocephalus (9.6%), grade 3 cerebrospinal fluid (CSF) leak (19.2%), and grade 3 CSF/brain infection (13.4%). CONCLUSION: The efficacy of implanted Gliadel wafers may be improved with the addition of O6-BG. Although systemically administered O6-BG can be coadministered with Gliadel wafers safely, it may increase the risk of hydrocephalus, CSF leak, and CSF/brain infection. Future trials are required to verify that inhibition of tumor AGT levels by O6-BG results in increased efficacy of Gliadel wafers without added toxicity.

Authors
Quinn, JA; Jiang, SX; Carter, J; Reardon, DA; Desjardins, A; Vredenburgh, JJ; Rich, JN; Gururangan, S; Friedman, AH; Bigner, DD; Sampson, JH; McLendon, RE; Herndon, JE; Threatt, S; Friedman, HS
MLA Citation
Quinn, JA, Jiang, SX, Carter, J, Reardon, DA, Desjardins, A, Vredenburgh, JJ, Rich, JN, Gururangan, S, Friedman, AH, Bigner, DD, Sampson, JH, McLendon, RE, Herndon, JE, Threatt, S, and Friedman, HS. "Phase II trial of Gliadel plus O6-benzylguanine in adults with recurrent glioblastoma multiforme." Clin Cancer Res 15.3 (February 1, 2009): 1064-1068.
PMID
19188181
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
3
Publish Date
2009
Start Page
1064
End Page
1068
DOI
10.1158/1078-0432.CCR-08-2130

Aptamers selected against the unglycosylated EGFRvIII ectodomain and delivered intracellularly reduce membrane-bound EGFRvIII and induce apoptosis.

Epidermal growth factor receptor variant III (EGFRvIII) is a glycoprotein uniquely expressed in glioblastoma, but not in normal brain tissues. To develop targeted therapies for brain tumors, we selected RNA aptamers against the histidine-tagged EGFRvIII ectodomain, using an Escherichia coli system for protein expression and purification. Representative aptamer E21 has a dissociation constant (Kd) of 33x10(-9) m, and exhibits high affinity and specificity for EGFRvIII in ELISA and surface plasmon resonance assays. However, selected aptamers cannot bind the same protein expressed from eukaryotic cells because glycosylation, a post-translational modification present only in eukaryotic systems, significantly alters the structure of the target protein. By transfecting EGFRvIII aptamers into cells, we find that membrane-bound, glycosylated EGFRvIII is reduced and the percentage of cells undergoing apoptosis is increased. We postulate that transfected aptamers can interact with newly synthesized EGFRvIII, disrupt proper glycosylation, and reduce the amount of mature EGFRvIII reaching the cell surface. Our work establishes the feasibility of disrupting protein post-translational modifications in situ with aptamers. This finding is useful for elucidating the function of proteins of interest with various modifications, as well as dissecting signal transduction pathways.

Authors
Liu, Y; Kuan, C-T; Mi, J; Zhang, X; Clary, BM; Bigner, DD; Sullenger, BA
MLA Citation
Liu, Y, Kuan, C-T, Mi, J, Zhang, X, Clary, BM, Bigner, DD, and Sullenger, BA. "Aptamers selected against the unglycosylated EGFRvIII ectodomain and delivered intracellularly reduce membrane-bound EGFRvIII and induce apoptosis." Biol Chem 390.2 (February 2009): 137-144.
PMID
19040357
Source
pubmed
Published In
Biological Chemistry
Volume
390
Issue
2
Publish Date
2009
Start Page
137
End Page
144
DOI
10.1515/BC.2009.022

In tribute to Mike Traynor (1939-2009)

Authors
Bigner, DD
MLA Citation
Bigner, DD. "In tribute to Mike Traynor (1939-2009)." Neuro-Oncology 11.6 (2009): 724--.
Source
scival
Published In
Neuro-Oncology
Volume
11
Issue
6
Publish Date
2009
Start Page
724-
DOI
10.1215/15228517-2009-094

Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma

We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly that of histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determination of stem cell fates and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing and blocking the state of histone lysine methylation, particularly at H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma. © 2009 Nature America, Inc. All rights reserved.

Authors
Northcott, PA; Nakahara, Y; Wu, X; Feuk, L; Ellison, DW; Croul, S; Mack, S; Kongkham, PN; Peacock, J; Dubuc, A; Ra, Y-S; Zilberberg, K; Mcleod, J; Scherer, SW; Rao, JS; Eberhart, CG; Grajkowska, W; Gillespie, Y; Lach, B; Grundy, R; Pollack, IF; Hamilton, RL; Meter, TV; Carlotti, CG; Boop, F; Bigner, D; Gilbertson, RJ; Rutka, JT; Taylor, MD
MLA Citation
Northcott, PA, Nakahara, Y, Wu, X, Feuk, L, Ellison, DW, Croul, S, Mack, S, Kongkham, PN, Peacock, J, Dubuc, A, Ra, Y-S, Zilberberg, K, Mcleod, J, Scherer, SW, Rao, JS, Eberhart, CG, Grajkowska, W, Gillespie, Y, Lach, B, Grundy, R, Pollack, IF, Hamilton, RL, Meter, TV, Carlotti, CG, Boop, F, Bigner, D, Gilbertson, RJ, Rutka, JT, and Taylor, MD. "Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma." Nature Genetics 41.4 (2009): 465-472.
PMID
19270706
Source
scival
Published In
Nature Genetics
Volume
41
Issue
4
Publish Date
2009
Start Page
465
End Page
472
DOI
10.1038/ng.336

Mutational inactivation of PTPRD in glioblastoma multiforme and malignant melanoma.

An additional tumor suppressor gene on chromosome 9p telomeric to the CDKN2A/B locus has long been postulated to exist. Using Affymetrix 250K single nucleotide polymorphism arrays to screen for copy number changes in glioblastoma multiforme (GBM), we detected a high frequency of deletions of the PTPRD gene, which encodes a receptor protein tyrosine phosphatase at chromosome 9p23-24.1. Missense and nonsense mutations of PTPRD were identified in a subset of the samples lacking deletions, including an inherited mutation with somatic loss of the wild-type allele. We then sequenced the gene in melanoma and identified 10 somatic mutations in 7 of 57 tumors (12%). Reconstitution of PTPRD expression in GBM and melanoma cells harboring deletions or mutations led to growth suppression and apoptosis that was alleviated by both the somatic and constitutional mutations. These data implicate PTPRD in the pathogenesis of tumors of neuroectodermal origin and, when taken together with other recent reports of PTPRD mutations in adenocarcinoma of the colon and lung, suggest that PTPRD may be one of a select group of tumor suppressor genes that are inactivated in a wide range of common human tumor types.

Authors
Solomon, DA; Kim, J-S; Cronin, JC; Sibenaller, Z; Ryken, T; Rosenberg, SA; Ressom, H; Jean, W; Bigner, D; Yan, H; Samuels, Y; Waldman, T
MLA Citation
Solomon, DA, Kim, J-S, Cronin, JC, Sibenaller, Z, Ryken, T, Rosenberg, SA, Ressom, H, Jean, W, Bigner, D, Yan, H, Samuels, Y, and Waldman, T. "Mutational inactivation of PTPRD in glioblastoma multiforme and malignant melanoma." Cancer Res 68.24 (December 15, 2008): 10300-10306.
PMID
19074898
Source
pubmed
Published In
Cancer Research
Volume
68
Issue
24
Publish Date
2008
Start Page
10300
End Page
10306
DOI
10.1158/0008-5472.CAN-08-3272

Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines.

The epidermal growth factor receptor variant III (EGFRvIII) is a consistent tumor-specific mutation that is widely expressed in glioblastoma multiforme (GBM) and other neoplasms. As such it represents a truly tumor-specific target for antitumor immunotherapy. Although endogenous humoral responses to EGFRvIII have been reported in patients with EGFRvIII-expressing breast cancer, it is not known whether de novo responses can be generated or endogenous responses enhanced with an EGFRvIII-specific vaccine. To assess this in clinical trials, we have developed and validated an immunoassay to measure and isolate anti-EGFRvIII and anti-KLH antibodies from the serum of patients vaccinated with an EGFRvIII-specific peptide (PEPvIII) conjugated to keyhole limpet hemocyanin (KLH). Using magnetic beads with immobilized antigen we captured and detected anti-EGFRvIII and anti-KLH antibodies in serum from patients before and after vaccinations. Using this assay, we found that significant levels of antibody for tumor-specific antigen EGFRvIII (>4 microg/mL) and KLH could be induced after vaccination with PEPvIII-KLH.

Authors
Schmittling, RJ; Archer, GE; Mitchell, DA; Heimberger, A; Pegram, C; Herndon, JE; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Schmittling, RJ, Archer, GE, Mitchell, DA, Heimberger, A, Pegram, C, Herndon, JE, Friedman, HS, Bigner, DD, and Sampson, JH. "Detection of humoral response in patients with glioblastoma receiving EGFRvIII-KLH vaccines." J Immunol Methods 339.1 (November 30, 2008): 74-81.
PMID
18775433
Source
pubmed
Published In
Journal of Immunological Methods
Volume
339
Issue
1
Publish Date
2008
Start Page
74
End Page
81
DOI
10.1016/j.jim.2008.08.004

Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas.

PURPOSE: Although patients with newly diagnosed WHO grade 3 malignant glioma have a more favorable prognosis than those with WHO grade 4 malignant glioma, salvage therapies following recurrence offer essentially palliative benefit. We did a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan for patients with recurrent grade 3 malignant glioma. EXPERIMENTAL DESIGN: Upon documentation of adequate safety among an initial cohort of nine patients treated with bevacizumab (10 mg/kg) and irinotecan every 14 days, a second cohort (n=24) was treated with bevacizumab (15 mg/kg) every 3 weeks with irinotecan on days 1, 8, 22, and 29 of each 42-day cycle. For both cohorts, the dose of irinotecan was 340 mg/m(2) for patients on enzyme-inducing antiepileptic drugs (EIAED) and 125 mg/m(2) for patients not on EIAEDs. After each 6-week cycle, patients were evaluated with a physical examination and magnetic resonance imaging. RESULTS: The 6-month progression-free survival was 55% (95% confidence interval, 36-70%). The 6-month overall survival was 79% (95% confidence interval, 61-89%). Twenty patients (61%) had at least a partial response. Outcome did not differ between the two treatment cohorts. Significant adverse events were infrequent and included a central nervous system hemorrhage in one patient, and one patient who developed thrombotic thrombocytopenic purpura. CONCLUSION: Bevacizumab and irinotecan is an active regimen with acceptable toxicity for patients with recurrent WHO grade 3 malignant glioma.

Authors
Desjardins, A; Reardon, DA; Herndon, JE; Marcello, J; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Sampson, J; Bailey, L; Bigner, DD; Friedman, AH; Friedman, HS; Vredenburgh, JJ
MLA Citation
Desjardins, A, Reardon, DA, Herndon, JE, Marcello, J, Quinn, JA, Rich, JN, Sathornsumetee, S, Gururangan, S, Sampson, J, Bailey, L, Bigner, DD, Friedman, AH, Friedman, HS, and Vredenburgh, JJ. "Bevacizumab plus irinotecan in recurrent WHO grade 3 malignant gliomas." Clin Cancer Res 14.21 (November 1, 2008): 7068-7073.
PMID
18981004
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
21
Publish Date
2008
Start Page
7068
End Page
7073
DOI
10.1158/1078-0432.CCR-08-0260

Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma.

Conventional therapies for malignant gliomas (MGs) fail to target tumor cells exclusively, such that their efficacy is ultimately limited by non-specific toxicity. Immunologic targeting of tumor-specific gene mutations, however, may allow more precise eradication of neoplastic cells. The epidermal growth factor receptor variant III (EGFRvIII) is a consistent tumor-specific mutation that is widely expressed in MGs and other neoplasms. This mutation encodes a constitutively active tyrosine kinase that enhances tumorgenicity and migration and confers radiation and chemotherapeutic resistance. This in-frame deletion mutation splits a codon resulting in the creation of a novel glycine at the fusion junction between normally distant parts of the molecule and producing a sequence re-arrangement which creates a tumor-specific epitope for cellular or humoral immunotherapy in patients with MGs. We have previously shown that vaccination with a peptide that spans the EGFRvIII fusion junction is an efficacious immunotherapy in syngeneic murine models, but patients with MGs have a profound immunosuppression that may inhibit the ability of antigen presenting cells (APCs), even those generated ex vivo, to induce EGFRvIII-specific immune responses. In this report, we summarize our results in humans targeting this mutation in two consecutive and one multi-institutional Phase II immunotherapy trials. These trials demonstrated that vaccines targeting EGFRvIII are capable of inducing potent T- and B-cell immunity in these patients, and lead to an unexpectedly long survival time. Most importantly, vaccines targeting EGFRvIII were universally successful at eliminating tumor cells expressing the targeted antigen without any evidence of symptomatic collateral toxicity. These studies establish the tumor-specific EGFRvIII mutation as a novel target for humoral- and cell-mediated immunotherapy in a variety of cancers. The recurrence of EGFRvIII-negative tumors in our patients, however, highlights the need for targeting a broader repertoire of tumor-specific antigens.

Authors
Sampson, JH; Archer, GE; Mitchell, DA; Heimberger, AB; Bigner, DD
MLA Citation
Sampson, JH, Archer, GE, Mitchell, DA, Heimberger, AB, and Bigner, DD. "Tumor-specific immunotherapy targeting the EGFRvIII mutation in patients with malignant glioma." Semin Immunol 20.5 (October 2008): 267-275. (Review)
PMID
18539480
Source
pubmed
Published In
Seminars in Immunology
Volume
20
Issue
5
Publish Date
2008
Start Page
267
End Page
275
DOI
10.1016/j.smim.2008.04.001

BEVACIZUMAB IN COMBINATION WITH TEMOZOLOMIDE AND RADIATION THERAPY FOLLOWED BY BEVACIZUMAB, TEMOZOLOMIDE, AND IRINOTECAN FOR NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME

Authors
Vredenburgh, J; Desjardins, A; Reardon, D; Rich, J; Kirkpatrick, J; Gururangan, S; Bailey, L; Friedman, A; Bigner, D; Friedman, H
MLA Citation
Vredenburgh, J, Desjardins, A, Reardon, D, Rich, J, Kirkpatrick, J, Gururangan, S, Bailey, L, Friedman, A, Bigner, D, and Friedman, H. "BEVACIZUMAB IN COMBINATION WITH TEMOZOLOMIDE AND RADIATION THERAPY FOLLOWED BY BEVACIZUMAB, TEMOZOLOMIDE, AND IRINOTECAN FOR NEWLY DIAGNOSED GLIOBLASTOMA MULTIFORME." October 2008.
Source
wos-lite
Published In
Neuro-Oncology
Volume
10
Issue
5
Publish Date
2008
Start Page
836
End Page
837

THE POSITIVE INFLUENCE OF TEMOZOLOMIDE ON THE HUMORAL AND CELL-MEDIATED (DTH) RESPONSES TO EGFRVIII-TARGETED VACCINE (CDX-110) IN PATIENTS WITH GBM

Authors
Archer, G; Heimberger, A; Bigner, D; Davis, T; Friedman, H; Friedman, A; Keler, T; Mitchell, D; Reardon, D; Sawaya, R; Vredenburgh, J; Yung, WKA; Rich, J; Gilbert, MR; Desjardins, A; Sampson, J
MLA Citation
Archer, G, Heimberger, A, Bigner, D, Davis, T, Friedman, H, Friedman, A, Keler, T, Mitchell, D, Reardon, D, Sawaya, R, Vredenburgh, J, Yung, WKA, Rich, J, Gilbert, MR, Desjardins, A, and Sampson, J. "THE POSITIVE INFLUENCE OF TEMOZOLOMIDE ON THE HUMORAL AND CELL-MEDIATED (DTH) RESPONSES TO EGFRVIII-TARGETED VACCINE (CDX-110) IN PATIENTS WITH GBM." October 2008.
Source
wos-lite
Published In
Neuro-Oncology
Volume
10
Issue
5
Publish Date
2008
Start Page
810
End Page
810

LIGAND-DEPENDENT ACTIVATION OF THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) INDUCES EARLY DRUG RESISTANCE IN BRAIN TUMOR CELLS VIA ACTIVATION OF ITS DOWNSTREAM TARGET GLUTATHIONE S-TRANSFERASE P1

Authors
Okamura, T; Singh, S; Bigner, D; Ali-Osman, F
MLA Citation
Okamura, T, Singh, S, Bigner, D, and Ali-Osman, F. "LIGAND-DEPENDENT ACTIVATION OF THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) INDUCES EARLY DRUG RESISTANCE IN BRAIN TUMOR CELLS VIA ACTIVATION OF ITS DOWNSTREAM TARGET GLUTATHIONE S-TRANSFERASE P1." October 2008.
Source
wos-lite
Published In
Neuro-Oncology
Volume
10
Issue
5
Publish Date
2008
Start Page
782
End Page
782

An integrated genomic analysis of human glioblastoma multiforme.

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.

Authors
Parsons, DW; Jones, S; Zhang, X; Lin, JC-H; Leary, RJ; Angenendt, P; Mankoo, P; Carter, H; Siu, I-M; Gallia, GL; Olivi, A; McLendon, R; Rasheed, BA; Keir, S; Nikolskaya, T; Nikolsky, Y; Busam, DA; Tekleab, H; Diaz, LA; Hartigan, J; Smith, DR; Strausberg, RL; Marie, SKN; Shinjo, SMO; Yan, H; Riggins, GJ; Bigner, DD; Karchin, R; Papadopoulos, N; Parmigiani, G; Vogelstein, B; Velculescu, VE; Kinzler, KW
MLA Citation
Parsons, DW, Jones, S, Zhang, X, Lin, JC-H, Leary, RJ, Angenendt, P, Mankoo, P, Carter, H, Siu, I-M, Gallia, GL, Olivi, A, McLendon, R, Rasheed, BA, Keir, S, Nikolskaya, T, Nikolsky, Y, Busam, DA, Tekleab, H, Diaz, LA, Hartigan, J, Smith, DR, Strausberg, RL, Marie, SKN, Shinjo, SMO, Yan, H, Riggins, GJ, Bigner, DD, Karchin, R, Papadopoulos, N, Parmigiani, G, Vogelstein, B, Velculescu, VE, and Kinzler, KW. "An integrated genomic analysis of human glioblastoma multiforme." Science 321.5897 (September 26, 2008): 1807-1812.
PMID
18772396
Source
pubmed
Published In
Science
Volume
321
Issue
5897
Publish Date
2008
Start Page
1807
End Page
1812
DOI
10.1126/science.1164382

Mismatch repair deficiency does not mediate clinical resistance to temozolomide in malignant glioma.

PURPOSE: A major mechanism of resistance to methylating agents, including temozolomide, is the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT). Preclinical data indicates that defective DNA mismatch repair (MMR) results in tolerance to temozolomide regardless of AGT activity. The purpose of this study was to determine the role of MMR deficiency in mediating resistance in samples from patients with both newly diagnosed malignant gliomas and those who have failed temozolomide therapy. EXPERIMENTAL DESIGN: The roles of AGT and MMR deficiency in mediating resistance in glioblastoma multiforme were assessed by immunohistochemistry and microsatellite instability (MSI), respectively. The mutation status of the MSH6 gene, a proposed correlate of temozolomide resistance, was determined by direct sequencing and compared with data from immunofluorescent detection of MSH6 protein and reverse transcription-PCR amplification of MSH6 RNA. RESULTS: Seventy percent of newly diagnosed and 78% of failed-therapy glioblastoma multiforme samples expressed nuclear AGT protein in > or = 20% of cells analyzed, suggesting alternate means of resistance in 20% to 30% of cases. Single loci MSI was observed in 3% of patient samples; no sample showed the presence of high MSI. MSI was not shown to correlate with MSH6 mutation or loss of MSH6 protein expression. CONCLUSIONS: Although high AGT levels may mediate resistance in a portion of these samples, MMR deficiency does not seem to be responsible for mediating temozolomide resistance in adult malignant glioma. Accordingly, the presence of a fraction of samples exhibiting both low AGT expression and MMR proficiency suggests that additional mechanisms of temozolomide resistance are operational in the clinic.

Authors
Maxwell, JA; Johnson, SP; McLendon, RE; Lister, DW; Horne, KS; Rasheed, A; Quinn, JA; Ali-Osman, F; Friedman, AH; Modrich, PL; Bigner, DD; Friedman, HS
MLA Citation
Maxwell, JA, Johnson, SP, McLendon, RE, Lister, DW, Horne, KS, Rasheed, A, Quinn, JA, Ali-Osman, F, Friedman, AH, Modrich, PL, Bigner, DD, and Friedman, HS. "Mismatch repair deficiency does not mediate clinical resistance to temozolomide in malignant glioma." Clin Cancer Res 14.15 (August 1, 2008): 4859-4868.
PMID
18676759
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
15
Publish Date
2008
Start Page
4859
End Page
4868
DOI
10.1158/1078-0432.CCR-07-4807

Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors.

The purpose of this study is to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and intracerebral distribution of a recombinant toxin (TP-38) targeting the epidermal growth factor receptor in patients with recurrent malignant brain tumors using the intracerebral infusion technique of convection-enhanced delivery (CED). Twenty patients were enrolled and stratified for dose escalation by the presence of residual tumor from 25 to 100 ng/ml in a 40-ml infusion volume. In the last eight patients, coinfusion of (123)I-albumin was performed to monitor distribution within the brain. The MTD was not reached in this study. Dose escalation was stopped at 100 ng/ml due to inconsistent drug delivery as evidenced by imaging the coinfused (123)I-albumin. Two DLTs were seen, and both were neurologic. Median survival after TP-38 was 28 weeks (95% confidence interval, 26.5-102.8). Of 15 patients treated with residual disease, two (13.3%) demonstrated radiographic responses, including one patient with glioblastoma multiforme who had a nearly complete response and remains alive >260 weeks after therapy. Coinfusion of (123)I-albumin demonstrated that high concentrations of the infusate could be delivered >4 cm from the catheter tip. However, only 3 of 16 (19%) catheters produced intraparenchymal infusate distribution, while the majority leaked infusate into the cerebrospinal fluid spaces. Intracerebral CED of TP-38 was well tolerated and produced some durable radiographic responses at doses

Authors
Sampson, JH; Akabani, G; Archer, GE; Berger, MS; Coleman, RE; Friedman, AH; Friedman, HS; Greer, K; Herndon, JE; Kunwar, S; McLendon, RE; Paolino, A; Petry, NA; Provenzale, JM; Reardon, DA; Wong, TZ; Zalutsky, MR; Pastan, I; Bigner, DD
MLA Citation
Sampson, JH, Akabani, G, Archer, GE, Berger, MS, Coleman, RE, Friedman, AH, Friedman, HS, Greer, K, Herndon, JE, Kunwar, S, McLendon, RE, Paolino, A, Petry, NA, Provenzale, JM, Reardon, DA, Wong, TZ, Zalutsky, MR, Pastan, I, and Bigner, DD. "Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors." Neuro Oncol 10.3 (June 2008): 320-329.
PMID
18403491
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
3
Publish Date
2008
Start Page
320
End Page
329
DOI
10.1215/15228517-2008-012

Effect of EGFRvIII-targeted vaccine (CDX-110) on immune response and TTP when given with simultaneous standard and continuous temozolomide in patients with GBM

Authors
Sampson, JH; Archer, GE; Bigner, DD; Davis, T; Friedman, HS; Keler, T; Mitchell, DA; Reardon, DA; Sawaya, R; Heimberger, AB
MLA Citation
Sampson, JH, Archer, GE, Bigner, DD, Davis, T, Friedman, HS, Keler, T, Mitchell, DA, Reardon, DA, Sawaya, R, and Heimberger, AB. "Effect of EGFRvIII-targeted vaccine (CDX-110) on immune response and TTP when given with simultaneous standard and continuous temozolomide in patients with GBM." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

Efficacy of a phase II vaccine targeting Cytomegalovirus antigens in newly diagnosed GBM

Authors
Mitchell, D; Archer, GE; Bigner, DD; Friedman, HS; Lally-Goss, D; II, HJE; McGehee, S; McLendon, R; Reardon, DA; Sampson, JH
MLA Citation
Mitchell, D, Archer, GE, Bigner, DD, Friedman, HS, Lally-Goss, D, II, HJE, McGehee, S, McLendon, R, Reardon, DA, and Sampson, JH. "Efficacy of a phase II vaccine targeting Cytomegalovirus antigens in newly diagnosed GBM." JOURNAL OF CLINICAL ONCOLOGY 26.15 (May 20, 2008).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
26
Issue
15
Publish Date
2008

The gene expression profiles of medulloblastoma cell lines resistant to preactivated cyclophosphamide.

The total expression profiles of two medulloblastoma cell lines resistant to the preactivated form of cyclophosphamide (4-hydroperoxycyclophosphamide, 4-HC) were examined using the Affymetrix GeneChip U133A array. Our primary objective was to look for possible genes, other than the well-studied aldehyde dehydrogenases (ALDH) that may be involved in cyclophosphamide (CP) resistance in medulloblastomas. We present here the lists of the most highly upregulated [30 for D341 MED (4-HCR); 20 for D283 MED (4-HCR)] and downregulated [19 for D341 MED (4-HCR); 15 for D283 MED (4-HCR)] genes which may be involved in conferring CP-resistance to the two medullobalstoma cell lines. The lists of genes from the two sublines almost had no overlap, suggesting different mechanisms of CP-resistance. One of the most noteworthy upregulated gene is TAP1 [90-fold increase in D341 MED (4-HCR) relative to D341 MED]. TAP1, a protein belonging to the ABC transporter family is normally involved in major histocompatibility class I (MHC I) antigen processing. This suggests the possible role of multidrug resistance (MDR), albeit atypical (which means it does not involve the usual MDR1 and MRP glycoproteins), in medulloblastoma's CP-resistance. Apart from TAP1, a number of other genes involved in MHC1 processing were upregulated in D341 MED (4HCR). D341 MED (4-HCR) also had a 20-fold increase in the expression of the aldo-keto reductase gene, AKR1B10, which may deactivate the reactive cyclophosphamide metabolite, aldophosphamide. For D283 MED (4-HCR), the most notable increase in expression is that of ALDH1B1, a member of the aldehyde dehydrogenase (ALDH) family of proteins.

Authors
Bacolod, MD; Lin, SM; Johnson, SP; Bullock, NS; Colvin, M; Bigner, DD; Friedman, HS
MLA Citation
Bacolod, MD, Lin, SM, Johnson, SP, Bullock, NS, Colvin, M, Bigner, DD, and Friedman, HS. "The gene expression profiles of medulloblastoma cell lines resistant to preactivated cyclophosphamide." Curr Cancer Drug Targets 8.3 (May 2008): 172-179.
PMID
18473730
Source
pubmed
Published In
Current cancer drug targets
Volume
8
Issue
3
Publish Date
2008
Start Page
172
End Page
179

Immunotherapy against angiogenesis-associated targets: evidence and implications for the treatment of malignant glioma.

Angiogenesis, the growth of new blood vessels from previously existing vasculature, is a requirement for tumor growth and metastasis. The first US FDA-approved drugs targeting angiogenesis have shown potential in the treatment of malignant gliomas. Immunotherapy as a treatment modality lends itself well to specifically targeting angiogenesis in tumors and may represent a powerful tool in the treatment of malignant gliomas. This review focuses on developments in immunotherapy targeting angiogenesis and tumor-vascular-specific endothelial cells using a variety of immunotherapeutic strategies including monoclonal antibodies and conjugated immunotoxins, as well as cellular, peptide, DNA and dendritic cell vaccines.

Authors
Everson, RG; Graner, MW; Gromeier, M; Vredenburgh, JJ; Desjardins, A; Reardon, DA; Friedman, HS; Friedman, AH; Bigner, DD; Sampson, JH
MLA Citation
Everson, RG, Graner, MW, Gromeier, M, Vredenburgh, JJ, Desjardins, A, Reardon, DA, Friedman, HS, Friedman, AH, Bigner, DD, and Sampson, JH. "Immunotherapy against angiogenesis-associated targets: evidence and implications for the treatment of malignant glioma." Expert Rev Anticancer Ther 8.5 (May 2008): 717-732. (Review)
PMID
18471045
Source
pubmed
Published In
Expert Review of Anticancer Therapy
Volume
8
Issue
5
Publish Date
2008
Start Page
717
End Page
732
DOI
10.1586/14737140.8.5.717

Identification of p18 INK4c as a tumor suppressor gene in glioblastoma multiforme.

Genomic alterations leading to aberrant activation of cyclin/cyclin-dependent kinase (cdk) complexes drive the pathogenesis of many common human tumor types. In the case of glioblastoma multiforme (GBM), these alterations are most commonly due to homozygous deletion of p16(INK4a) and less commonly due to genomic amplifications of individual genes encoding cyclins or cdks. Here, we describe deletion of the p18(INK4c) cdk inhibitor as a novel genetic alteration driving the pathogenesis of GBM. Deletions of p18(INK4c) often occurred in tumors also harboring homozygous deletions of p16(INK4a). Expression of p18(INK4c) was completely absent in 43% of GBM primary tumors studied by immunohistochemistry. Lentiviral reconstitution of p18(INK4c) expression at physiologic levels in p18(INK4c)-deficient but not p18(INK4c)-proficient GBM cells led to senescence-like G(1) cell cycle arrest. These studies identify p18(INK4c) as a GBM tumor suppressor gene, revealing an additional mechanism leading to aberrant activation of cyclin/cdk complexes in this terrible malignancy.

Authors
Solomon, DA; Kim, J-S; Jenkins, S; Ressom, H; Huang, M; Coppa, N; Mabanta, L; Bigner, D; Yan, H; Jean, W; Waldman, T
MLA Citation
Solomon, DA, Kim, J-S, Jenkins, S, Ressom, H, Huang, M, Coppa, N, Mabanta, L, Bigner, D, Yan, H, Jean, W, and Waldman, T. "Identification of p18 INK4c as a tumor suppressor gene in glioblastoma multiforme." Cancer Res 68.8 (April 15, 2008): 2564-2569.
PMID
18381405
Source
pubmed
Published In
Cancer Research
Volume
68
Issue
8
Publish Date
2008
Start Page
2564
End Page
2569
DOI
10.1158/0008-5472.CAN-07-6388

A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost.

The purpose of this study was to determine the feasibility and assess the efficacy and toxicity, among newly diagnosed malignant glioma patients, of administering (131)I-labeled murine antitenascin monoclonal antibody 81C6 ((131)I-81C6) into a surgically created resection cavity (SCRC) to achieve a patient-specific, 44-Gy boost to the 2-cm SCRC margin. A radioactivity dose of (131)I-81C6 calculated to achieve a 44-Gy boost to the SCRC was administered, followed by conventional external beam radiotherapy (XRT) and chemotherapy. Twenty-one patients were enrolled in the study: 16 with glioblastoma multiforme (GBM) and 5 with anaplastic astrocytoma. Twenty patients received the targeted 44-Gy boost (+/-10%) to the SCRC. Attributable toxicity was mild and limited to reversible grade 3 neutropenia or thrombocytopenia (n = 3; 14%), CNS wound infections (n = 3; 14%), and headache (n = 2; 10%). With a median follow-up of 151 weeks, median overall survival times for all patients and those with GBM are 96.6 and 90.6 weeks, respectively; 87% of GBM patients are alive at 1 year. It is feasible to consistently achieve a 44-Gy boost dose to the SCRC margin with patient-specific dosing of (131)I-81C6. Our study regimen ((131)I-81C6 + XRT + temozolomide) was well tolerated and had encouraging survival. To determine if selection of good-prognosis patients affects outcome associated with this approach, the U.S. Food and Drug Administration has approved a trial randomizing newly diagnosed GBM patients to either our study regimen or standard XRT plus temozolomide.

Authors
Reardon, DA; Zalutsky, MR; Akabani, G; Coleman, RE; Friedman, AH; Herndon, JE; McLendon, RE; Pegram, CN; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Guruangan, S; Boulton, S; Raynor, RH; Dowell, JM; Wong, TZ; Zhao, X-G; Friedman, HS; Bigner, DD
MLA Citation
Reardon, DA, Zalutsky, MR, Akabani, G, Coleman, RE, Friedman, AH, Herndon, JE, McLendon, RE, Pegram, CN, Quinn, JA, Rich, JN, Vredenburgh, JJ, Desjardins, A, Guruangan, S, Boulton, S, Raynor, RH, Dowell, JM, Wong, TZ, Zhao, X-G, Friedman, HS, and Bigner, DD. "A pilot study: 131I-antitenascin monoclonal antibody 81c6 to deliver a 44-Gy resection cavity boost." Neuro Oncol 10.2 (April 2008): 182-189.
PMID
18287339
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
2
Publish Date
2008
Start Page
182
End Page
189
DOI
10.1215/15228517-2007-053

Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: case study.

Cytotoxic chemotherapy that induces lymphopenia is predicted to ablate the benefits of active antitumor immunization. Temozolomide is an effective chemotherapeutic agent for patients with glioblastoma multiforme, but it induces significant lymphopenia. Although there is monthly fluctuation of the white blood cell count, specifically the CD4 and CD8 counts, there was no cumulative decline in the patient described in this case report. Depriving patients of this agent, in order to treat with immunotherapy, is controversial. Despite conventional dogma, we demonstrated that chemotherapy and immunotherapy can be delivered concurrently without negating the effects of immunotherapy. In fact, the temozolomide-induced lymphopenia may prove to be synergistic with a peptide vaccine secondary to inhibition of regulatory T cells or their delayed recovery.

Authors
Heimberger, AB; Sun, W; Hussain, SF; Dey, M; Crutcher, L; Aldape, K; Gilbert, M; Hassenbusch, SJ; Sawaya, R; Schmittling, B; Archer, GE; Mitchell, DA; Bigner, DD; Sampson, JH
MLA Citation
Heimberger, AB, Sun, W, Hussain, SF, Dey, M, Crutcher, L, Aldape, K, Gilbert, M, Hassenbusch, SJ, Sawaya, R, Schmittling, B, Archer, GE, Mitchell, DA, Bigner, DD, and Sampson, JH. "Immunological responses in a patient with glioblastoma multiforme treated with sequential courses of temozolomide and immunotherapy: case study." Neuro Oncol 10.1 (February 2008): 98-103.
PMID
18079360
Source
pubmed
Published In
Neuro-Oncology
Volume
10
Issue
1
Publish Date
2008
Start Page
98
End Page
103
DOI
10.1215/15228517-2007-046

Utility of EGFR and PTEN numerical aberrations in the evaluation of diffusely infiltrating astrocytomas. Laboratory investigation.

OBJECT: Diffusely infiltrating astrocytomas are the most common primary brain tumors. As a group, they demonstrate an inherent tendency toward malignant progression. Histological grading using the guidelines of the World Health Organization (WHO) remains the gold standard for predicting the biological behavior of these tumors. Although useful, this grading system is often limited due to small sample sizes and the subjectivity in interpretation. Given the important roles for EGFR and PTEN in the malignant progression of astrocytomas, the authors hypothesized that the fraction of tumor cells with aberrations in these genetic loci would correlate with the histological grade. METHODS: The authors evaluated 217 consecutive diffusely infiltrating astrocytomas that were graded using the WHO guidelines, including 16 diffuse astrocytomas (WHO Grade II), 72 anaplastic astrocytomas ([AAs] WHO Grade III), and 129 glioblastomas multiforme ([GBMs] WHO Grade IV). Cases were evaluated quantitatively using dual-color fluorescence in situ hybridization with probes for the EGFR and PTEN loci and the centromeres of chromosomes 7 and 10. RESULTS: The population of tumor cells with polysomy of chromosome 7 and the EGFR locus and monosomy of chromosome 10 and the PTEN locus correlated significantly with histological grade. In particular, high-grade astrocytomas (that is, AAs and GBMs) had elevated fractions of tumor cells with polysomy of chromosome 7 and the EGFR locus and monosomy of chromosome 10 and the PTEN locus. Using these findings, the authors generated a mathematical model capable of subcategorizing high-grade astrocytomas. The successful model incorporated only the percentage of tumor cells with polysomy of EGFR and monosomy of PTEN, as well as patient age. The predictions of this model correlated with survival in a manner similar to histopathological grading. CONCLUSIONS: The findings presented in this study emphasize the utility of combining histological interpretation and molecular testing in the evaluation of infiltrating astrocytomas. These results underscore the utility of building a grading framework that combines histopathological and molecular analysis.

Authors
Mott, RT; Turner, KC; Bigner, DD; McLendon, RE
MLA Citation
Mott, RT, Turner, KC, Bigner, DD, and McLendon, RE. "Utility of EGFR and PTEN numerical aberrations in the evaluation of diffusely infiltrating astrocytomas. Laboratory investigation." J Neurosurg 108.2 (February 2008): 330-335.
PMID
18240930
Source
pubmed
Published In
Journal of neurosurgery
Volume
108
Issue
2
Publish Date
2008
Start Page
330
End Page
335
DOI
10.3171/JNS/2008/108/2/0330

Development of a real-time RT-PCR assay for detecting EGFRvIII in glioblastoma samples.

PURPOSE: Epidermal growth factor receptor variant III (EGFRvIII) is an oncogenic, constitutively active mutant form of the EGFR that is commonly expressed in glioblastoma and is also detected in a number of epithelial cancers. EGFRvIII presents a unique antigenic target for anti-EGFRvIII vaccines and it has been shown to modulate response to EGFR kinase inhibitor therapy. Thus, detection in clinical samples may be warranted. Existing patents preclude the use of anti-EGFRvIII antibodies for clinical detection. Further, frozen tissue is not routinely available, particularly for patients treated in the community. Thus, detection of EGFRvIII in formalin-fixed paraffin-embedded (FFPE) clinical samples is a major challenge. EXPERIMENTAL DESIGN: We developed a real-time reverse transcription-PCR (RT-PCR) assay for detecting EGFRvIII in FFPE samples and analyzed 59 FFPE glioblastoma clinical samples with paired frozen tissue from the same surgical resection. We assessed EGFRvIII protein expression by immunohistochemistry using two distinct specific anti-EGFRvIII antibodies and examined EGFR gene amplification by fluorescence in situ hybridization. RESULTS: The FFPE RT-PCR assay detected EGFRvIII in 16 of 59 (27%) samples, exclusively in cases with EGFR amplification, consistent with the expected frequency of this alteration. The FFPE RT-PCR assay was more sensitive and specific for detecting EGFRvIII than either of the two antibodies alone, or in combination, with a sensitivity of 93% (95% confidence interval, 0.78-1.00) and a specificity of 98% (95% confidence interval, 0.93-1.00). CONCLUSION: This assay will facilitate accurate assessment of EGFRvIII in clinical samples and may aid in the development of strategies for stratifying patients for EGFRvIII-directed therapies.

Authors
Yoshimoto, K; Dang, J; Zhu, S; Nathanson, D; Huang, T; Dumont, R; Seligson, DB; Yong, WH; Xiong, Z; Rao, N; Winther, H; Chakravarti, A; Bigner, DD; Mellinghoff, IK; Horvath, S; Cavenee, WK; Cloughesy, TF; Mischel, PS
MLA Citation
Yoshimoto, K, Dang, J, Zhu, S, Nathanson, D, Huang, T, Dumont, R, Seligson, DB, Yong, WH, Xiong, Z, Rao, N, Winther, H, Chakravarti, A, Bigner, DD, Mellinghoff, IK, Horvath, S, Cavenee, WK, Cloughesy, TF, and Mischel, PS. "Development of a real-time RT-PCR assay for detecting EGFRvIII in glioblastoma samples." Clin Cancer Res 14.2 (January 15, 2008): 488-493.
PMID
18223223
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
14
Issue
2
Publish Date
2008
Start Page
488
End Page
493
DOI
10.1158/1078-0432.CCR-07-1966

EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4+ and CD8+ T cells.

PURPOSE: Immunotoxins as anti-cancer therapeutics have several potential advantages over conventional agents including a high specificity, extraordinary potency, and a lack of an identified mechanism for resistance. It has been clearly demonstrated that Pseudomonas-based immunotoxins have a direct cytotoxic effect. However, delayed and often dramatic antitumor responses seen in human studies with targeted toxins led us to hypothesize that immunologic responses may be a secondary mechanism that enhances the therapeutic efficacy of these novel drugs. EXPERIMENTAL DESIGN: This hypothesis was tested in a murine system using an immunotoxin, MR1-1 [MR1-1(dsFv)-PE38KDEL], that targets a syngeneic murine homologue of the tumor-specific human epidermal growth factor mutation, EGFRvIII, expressed on a murine cell line. RESULTS: Intratumoral treatment with MR1-1 eliminated EGFRvIII-expressing tumors (P < 0.0001). The antitumor activity of MR1-1 was dependent on the expression of EGFRvIII on some, but not all tumors cells, and was significantly inhibited in the absence of CD4+ (P = 0.0193) and CD8+ (P = 0.0193) T cells. MR1-1 induced EGFRvIII-specific immunity (P < 0.0005) and produced long lasting immunity against tumors expressing EGFRvIII as well as EGFRvIII-negative tumors. CONCLUSIONS: These data suggest that immunotoxins may not be strictly dependent on direct cytotoxicity for their efficacy, but may also be potent inducers of antitumor immunity active even against cells that do not express the targeted antigen.

Authors
Ochiai, H; Archer, GE; Herndon, JE; Kuan, C-T; Mitchell, DA; Bigner, DD; Pastan, IH; Sampson, JH
MLA Citation
Ochiai, H, Archer, GE, Herndon, JE, Kuan, C-T, Mitchell, DA, Bigner, DD, Pastan, IH, and Sampson, JH. "EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4+ and CD8+ T cells." Cancer Immunol Immunother 57.1 (January 2008): 115-121.
PMID
17634939
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
57
Issue
1
Publish Date
2008
Start Page
115
End Page
121
DOI
10.1007/s00262-007-0363-7

Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6.

UNLABELLED: alpha-Particle-emitting radionuclides, such as (211)At, with a 7.2-h half-life, may be optimally suited for the molecularly targeted radiotherapy of strategically sensitive tumor sites, such as those in the central nervous system. Because of the much shorter range and more potent cytotoxicity of alpha-particles than of beta-particles, (211)At-labeled agents may be ideal for the eradication of tumor cells remaining after surgical debulking of malignant brain tumors. The main goal of this study was to investigate the feasibility and safety of this approach in patients with recurrent malignant brain tumors. METHODS: Chimeric antitenascin monoclonal antibody 81C6 (ch81C6) (10 mg) was labeled with 71-347 MBq of (211)At by use of N-succinimidyl 3-[(211)At]astatobenzoate. Eighteen patients were treated with (211)At-labeled ch81C6 ((211)At-ch81C6) administered into a surgically created resection cavity (SCRC) and then with salvage chemotherapy. Serial gamma-camera imaging and blood sampling over 24 h were performed. RESULTS: A total of 96.7% +/- 3.6% (mean +/- SD) of (211)At decays occurred in the SCRC, and the mean blood-pool percentage injected dose was < or = 0.3. No patient experienced dose-limiting toxicity, and the maximum tolerated dose was not identified. Six patients experienced grade 2 neurotoxicity within 6 wk of (211)At-ch81C6 administration; this neurotoxicity resolved fully in all but 1 patient. No toxicities of grade 3 or higher were attributable to the treatment. No patient required repeat surgery for radionecrosis. The median survival times for all patients, those with glioblastoma multiforme, and those with anaplastic astrocytoma or oligodendroglioma were 54, 52, and 116 wk, respectively. CONCLUSION: This study provides proof of concept for regional targeted radiotherapy with (211)At-labeled molecules in oncology. Specifically, the regional administration of (211)At-ch81C6 is feasible, safe, and associated with a promising antitumor benefit in patients with malignant central nervous system tumors.

Authors
Zalutsky, MR; Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; McLendon, RE; Wong, TZ; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, McLendon, RE, Wong, TZ, and Bigner, DD. "Clinical experience with alpha-particle emitting 211At: treatment of recurrent brain tumor patients with 211At-labeled chimeric antitenascin monoclonal antibody 81C6." J Nucl Med 49.1 (January 2008): 30-38.
PMID
18077533
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
49
Issue
1
Publish Date
2008
Start Page
30
End Page
38
DOI
10.2967/jnumed.107.046938

Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer. ©2008 Macmillan Publishers Limited. All rights reserved.

Authors
McLendon, R; Friedman, A; Bigner, D; Meir, EGV; Brat, DJ; Mastrogianakis, GM; Olson, JJ; Mikkelsen, T; Lehman, N; Aldape, K; Yung, WKA; Bogler, O; Weinstein, JN; VandenBerg, S; Berger, M; Prados, M; Muzny, D; Morgan, M; Scherer, S; Sabo, A; Nazareth, L; Lewis, L; Hall, O; Zhu, Y; Ren, Y; Alvi, O; Yao, J; Hawes, A; Jhangiani, S; Fowler, G; Lucas, AS; Kovar, C; Cree, A; Dinh, H; Santibanez, J; Joshi, V; Gonzalez-Garay, ML; Miller, CA; Milosavljevic, A; Donehower, L; Wheeler, DA; Gibbs, RA et al.
MLA Citation
McLendon, R, Friedman, A, Bigner, D, Meir, EGV, Brat, DJ, Mastrogianakis, GM, Olson, JJ, Mikkelsen, T, Lehman, N, Aldape, K, Yung, WKA, Bogler, O, Weinstein, JN, VandenBerg, S, Berger, M, Prados, M, Muzny, D, Morgan, M, Scherer, S, Sabo, A, Nazareth, L, Lewis, L, Hall, O, Zhu, Y, Ren, Y, Alvi, O, Yao, J, Hawes, A, Jhangiani, S, Fowler, G, Lucas, AS, Kovar, C, Cree, A, Dinh, H, Santibanez, J, Joshi, V, Gonzalez-Garay, ML, Miller, CA, Milosavljevic, A, Donehower, L, Wheeler, DA, and Gibbs, RA et al. "Comprehensive genomic characterization defines human glioblastoma genes and core pathways." Nature 455.7216 (2008): 1061-1068.
PMID
18772890
Source
scival
Published In
Nature
Volume
455
Issue
7216
Publish Date
2008
Start Page
1061
End Page
1068
DOI
10.1038/nature07385

GENETIC PROFILING IN TUMOR XENOGRAFTS FROM PAEDIATRIC GLIOMAS BY EXPRESSION AND HIGH RESOLUTION COMPARATIVE GENOMIC HYBRIDISATION MICROARRAYS

Authors
Karakoula, K; Potter, N; Keir, ST; Bigner, DD; Phipps, KP; Harkness, W; Hayward, R; Thompson, D; Jacques, TS; Harding, B; Thomas, DGT; Warr, TJ
MLA Citation
Karakoula, K, Potter, N, Keir, ST, Bigner, DD, Phipps, KP, Harkness, W, Hayward, R, Thompson, D, Jacques, TS, Harding, B, Thomas, DGT, and Warr, TJ. "GENETIC PROFILING IN TUMOR XENOGRAFTS FROM PAEDIATRIC GLIOMAS BY EXPRESSION AND HIGH RESOLUTION COMPARATIVE GENOMIC HYBRIDISATION MICROARRAYS." ANTICANCER RESEARCH 28.5C (2008): 3341-3341.
Source
wos-lite
Published In
Anticancer research
Volume
28
Issue
5C
Publish Date
2008
Start Page
3341
End Page
3341

O (4)-benzylfolic acid inactivates O (6)-alkylguanine-DNA alkyltransferase in brain tumor cell lines.

PURPOSE: The DNA repair protein, O (6)-alkylguanine-DNA alkyltransferase (AGT), is a primary source of tumor resistance to agents such as temozolomide and chloroethylnitrosoureas that form DNA lesions at the O (6)-position of guanines. To increase the efficacy of these drugs, pseudosubstrate inactivators of AGT such as O (6)-benzylguanine have been developed. A novel inactivator of AGT, O (4)-benzylfolic acid (O(4)-BFA), has been reported which is more potent and water soluble than O (6)-benzylguanine. Previous studies have suggested that uptake of O(4)-BFA is mediated by the folate receptor (FR), and, thus, its use may be limited to cells expressing FR. METHODS: We measured AGT activity in cell extracts from a panel of brain tumor cells exposed to O(4)-BFA. Inactivation of AGT by O(4)-BFA was measured in cells grown without folic acid as well as in cells grown in folic acid-containing media. Competitive binding studies were performed using purified FR to determine its affinity for O(4)-BFA. RESULTS: The observed IC(50) for O(4)-BFA in brain tumor cell lines ranged from 0.2 to 1.3 microM for cells grown in media containing 2.3 microM folic acid. At this concentration, folic acid would saturate the FR and the FR would be unable to take up O(4)-BFA. When cells were grown in folic acid free media, there was at most a 50% decrease in the observed IC(50)s, indicating that the FR was not essential for O(4)-BFA uptake. Competitive binding studies using purified FR confirmed that the IC(50) for O(4)-BFA is approximately 180 times greater than folic acid, i.e., it has a very weak affinity for FR. CONCLUSION: These results indicate that O(4)-BFA has potentially broad use as an inactivator of AGT as its use is not limited to tumors expressing high levels of FR.

Authors
Johnson, SP; Kamen, BA; Bigner, DD; Friedman, HS
MLA Citation
Johnson, SP, Kamen, BA, Bigner, DD, and Friedman, HS. "O (4)-benzylfolic acid inactivates O (6)-alkylguanine-DNA alkyltransferase in brain tumor cell lines." Cancer Chemother Pharmacol 60.6 (November 2007): 883-889.
PMID
17333191
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
60
Issue
6
Publish Date
2007
Start Page
883
End Page
889
DOI
10.1007/s00280-007-0435-6

Bevacizumab plus irinotecan in recurrent glioblastoma multiforme.

PURPOSE: The prognosis for patients with recurrent glioblastoma multiforme is poor, with a median survival of 3 to 6 months. We performed a phase II trial of bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in combination with irinotecan. PATIENTS AND METHODS: This phase II trial included two cohorts of patients. The initial cohort, comprising 23 patients, received bevacizumab at 10 mg/kg plus irinotecan every 2 weeks. The dose of irinotecan was based on the patient's anticonvulsant: Patients taking enzyme-inducing antiepileptic drugs (EIAEDs) received 340 mg/m2, and patients not taking EIAEDs received 125 mg/m2. After this regimen was deemed safe and effective, the irinotecan schedule was changed to an accepted brain tumor regimen of four doses in 6 weeks, in anticipation of a phase III randomized trial of irinotecan versus irinotecan and bevacizumab. The second cohort, comprising 12 patients, received bevacizumab 15 mg/kg every 21 days and irinotecan on days 1, 8, 22, and 29. Each cycle was 6 weeks long and concluded with patient evaluations, including magnetic resonance imaging. RESULTS: The 6-month progression-free survival among all 35 patients was 46% (95% CI, 32% to 66%). The 6-month overall survival was 77% (95% CI, 64% to 92%). Twenty of the 35 patients (57%; 95% CI, 39% to 74%) had at least a partial response. One patient developed a CNS hemorrhage, which occurred in his 10th cycle. Four patients developed thromboembolic complications (deep venous thrombosis and/or pulmonary emboli). CONCLUSION: Bevacizumab and irinotecan is an effective treatment for recurrent glioblastoma multiforme and has moderate toxicity.

Authors
Vredenburgh, JJ; Desjardins, A; Herndon, JE; Marcello, J; Reardon, DA; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Sampson, J; Wagner, M; Bailey, L; Bigner, DD; Friedman, AH; Friedman, HS
MLA Citation
Vredenburgh, JJ, Desjardins, A, Herndon, JE, Marcello, J, Reardon, DA, Quinn, JA, Rich, JN, Sathornsumetee, S, Gururangan, S, Sampson, J, Wagner, M, Bailey, L, Bigner, DD, Friedman, AH, and Friedman, HS. "Bevacizumab plus irinotecan in recurrent glioblastoma multiforme." J Clin Oncol 25.30 (October 20, 2007): 4722-4729.
PMID
17947719
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
30
Publish Date
2007
Start Page
4722
End Page
4729
DOI
10.1200/JCO.2007.12.2440

The heat shock response and chaperones/heat shock proteins in brain tumors: surface expression, release, and possible immune consequences.

The heat shock response is a highly conserved "stress response" mechanism used by cells to protect themselves from potentially damaging insults. It often involves the upregulated expression of chaperone and heat shock proteins (HSPs) to prevent damage and aggregation at the proteome level. Like most cancers, brain tumor cells often overexpress chaperones/HSPs, probably because of the stressful atmosphere in which tumors reside, but also because of the benefits of HSP cytoprotection. However, the cellular dynamics and localization of HSPs in either stressed or unstressed conditions has not been studied extensively in brain tumor cells. We have examined the changes in HSP expression and in cell surface/extracellular localization of selected brain tumor cell lines under heat shock or normal environments. We herein report that brain tumor cell lines have considerable heat shock responses or already high constitutive HSP levels; that those cells express various HSPs, chaperones, and at least one cochaperone on their cell surfaces; and that HSPs may be released into the extracellular environment, possibly as exosome vesicular content. In studies with a murine astrocytoma cell line, heat shock dramatically reduces tumorigenicity, possibly by an immune mechanism. Additional evidence indicative of an HSP-driven immune response comes from immunization studies using tumor-derived chaperone protein vaccines, which lead to antigen-specific immune responses and reduced tumor burden in treated mice. The heat shock response and HSPs in brain tumor cells may represent an area of vulnerability in our attempts to treat these recalcitrant and deadly tumors.

Authors
Graner, MW; Cumming, RI; Bigner, DD
MLA Citation
Graner, MW, Cumming, RI, and Bigner, DD. "The heat shock response and chaperones/heat shock proteins in brain tumors: surface expression, release, and possible immune consequences." J Neurosci 27.42 (October 17, 2007): 11214-11227.
PMID
17942716
Source
pubmed
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
27
Issue
42
Publish Date
2007
Start Page
11214
End Page
11227
DOI
10.1523/JNEUROSCI.3588-07.2007

Targeted alpha-particle radiotherapy with 211At-labeled monoclonal antibodies.

An attractive feature of targeted radionuclide therapy is the ability to select radionuclides and targeting vehicles with characteristics that are best suited for a particular clinical application. One combination that has been receiving increasing attention is the use of monoclonal antibodies (mAbs) specifically reactive to receptors and antigens that are expressed in tumor cells to selectively deliver the alpha-particle-emitting radiohalogen astatine-211 (211At) to malignant cell populations. Promising results have been obtained in preclinical models with multiple 211At-labeled mAbs; however, translation of the concept to the clinic has been slow. Impediments to this process include limited radionuclide availability, the need for suitable radiochemistry methods operant at high activity levels and lack of data concerning the toxicity of alpha-particle emitters in humans. Nonetheless, two clinical trials have been initiated to date with 211At-labeled mAbs, and others are planned for the near future.

Authors
Zalutsky, MR; Reardon, DA; Pozzi, OR; Vaidyanathan, G; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, Pozzi, OR, Vaidyanathan, G, and Bigner, DD. "Targeted alpha-particle radiotherapy with 211At-labeled monoclonal antibodies." Nucl Med Biol 34.7 (October 2007): 779-785. (Review)
PMID
17921029
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
34
Issue
7
Publish Date
2007
Start Page
779
End Page
785
DOI
10.1016/j.nucmedbio.2007.03.007

Targeted alpha-particle radiotherapy with At-211-labeled monoclonal antibodies

Authors
Zalutsky, MR; Reardon, DA; Pozzi, OR; Vaidyanathan, G; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, Pozzi, OR, Vaidyanathan, G, and Bigner, DD. "Targeted alpha-particle radiotherapy with At-211-labeled monoclonal antibodies." October 2007.
Source
wos-lite
Published In
Nuclear Medicine and Biology
Volume
34
Issue
7
Publish Date
2007
Start Page
779
End Page
785
DOI
10.1016/j.nuemedbio.2007.03.007

Characterization of brain tumor exosomes: Biology, biochemistry, immumology

Authors
Graner, M; Dechkovskaia, A; Wang, L; Cumming, I; Bigner, D
MLA Citation
Graner, M, Dechkovskaia, A, Wang, L, Cumming, I, and Bigner, D. "Characterization of brain tumor exosomes: Biology, biochemistry, immumology." October 2007.
Source
wos-lite
Published In
Neuro-Oncology
Volume
9
Issue
4
Publish Date
2007
Start Page
501
End Page
501

The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion.

Monotherapies have proven largely ineffective for the treatment of glioblastomas, suggesting that increased patient benefit may be achieved by combining therapies. Two protumorigenic pathways known to be active in glioblastoma include RAS/RAF/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT/target of rapamycin (TOR). We investigated the efficacy of a combination of novel low molecular weight inhibitors LBT613 and RAD001 (everolimus), which were designed to target RAF and TOR, respectively. LBT613 decreased phosphorylation of extracellular signal-regulated kinase 1 and 2, downstream effectors of RAF, in a human glioma cell line. RAD001 resulted in decreased phosphorylation of the TOR effector S6. To determine if targeting RAF and TOR activities could result in decreased protumorigenic glioma cellular behaviors, we evaluated the abilities of LBT613 and RAD001 to affect the proliferation, migration, and invasion of human glioma cells. Treatment with either LBT613 or RAD001 alone significantly decreased the proliferation of multiple human glioma cell lines. Furthermore, LBT613 and RAD001 in combination synergized to decrease glioma cell proliferation in association with G(1) cell cycle arrest. Glioma invasion is a critical contributor to tumor malignancy. The combination of LBT613 and RAD001 inhibited the invasion of human glioma cells through Matrigel to a greater degree than treatment with either drug alone. These data suggest that the combination of LBT613 and RAD001 reduces glioma cell proliferation and invasion and support examination of the combination of RAF and TOR inhibitors for the treatment of human glioblastoma patients.

Authors
Hjelmeland, AB; Lattimore, KP; Fee, BE; Shi, Q; Wickman, S; Keir, ST; Hjelmeland, MD; Batt, D; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Hjelmeland, AB, Lattimore, KP, Fee, BE, Shi, Q, Wickman, S, Keir, ST, Hjelmeland, MD, Batt, D, Bigner, DD, Friedman, HS, and Rich, JN. "The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion." Mol Cancer Ther 6.9 (September 2007): 2449-2457.
PMID
17766837
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
6
Issue
9
Publish Date
2007
Start Page
2449
End Page
2457
DOI
10.1158/1535-7163.MCT-07-0155

Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice.

VNP40101M, or 1,2-bis(methylsulfonyl)-1-(2-choloroethyl)-2-(methylamino)carbonylhydrazine (Cloretazine), is a bifunctional prodrug that belongs to a class of DNA-modifying agents-the sulfonylhydrazines-that has been synthesized and been shown to have activity against a wide spectrum of xenografts. The current study was designed to assess the activity of VNP40101M administered at a dose of 18 mg/kg daily for five days against a panel of human adult and pediatric CNS tumors growing subcutaneously or intracranially in athymic nude mice. The results demonstrated statistically significant (p < 0.05) growth delays of 15.0, 8.3, 51.0, 60+, 60+, and 60+ days in subcutaneous xenografts derived from childhood glioblastoma multiforme (D-456 MG), childhood ependymoma (D-528 EP and D-612 EP), childhood medulloblastoma (D-425 MED), and adult malignant glioma (D-245 MG and D-54 MG), respectively, with corresponding tumor regressions in 10 of 10, 4 of 10, 8 of 10, 9 of 10, 9 of 10, and 10 of 10 treated mice, respectively. Delayed toxicity was seen more than 60 days after treatment, with 23 deaths in 100 treated animals, despite a median weight loss of only 0.06%. In mice bearing intracranial D-245 MG xenografts, treatment with VNP40101M at a dose of 18 mg/kg daily for five days produced a 50% increase in median survival compared with controls. Additional experiments conducted against subcutaneous D-245 MG xenografts by using reduced doses of 13.5 or 9.0 mg/kg daily for five days demonstrated tumor growth delays of 82.2 and 53.5 days, with corresponding tumor regressions in 8 of 9 and 9 of 10 treated mice, respectively (all values, p < 0.001), with one toxic death. These findings suggest that VNP40101M is active in the treatment of a wide range of human central nervous system tumors and warrants translation to the clinic.

Authors
Badruddoja, MA; Keir, ST; King, I; Zeidner, J; Vredenburgh, JJ; Muhlbaier, LH; Bigner, DD; Friedman, HS
MLA Citation
Badruddoja, MA, Keir, ST, King, I, Zeidner, J, Vredenburgh, JJ, Muhlbaier, LH, Bigner, DD, and Friedman, HS. "Activity of VNP40101M (Cloretazine) in the treatment of CNS tumor xenografts in athymic mice." Neuro Oncol 9.3 (July 2007): 240-244.
PMID
17522334
Source
pubmed
Published In
Neuro-Oncology
Volume
9
Issue
3
Publish Date
2007
Start Page
240
End Page
244
DOI
10.1215/15228517-2007-011

Clinical utility of a patient-specific algorithm for simulating intracerebral drug infusions.

Convection-enhanced delivery (CED) is a novel drug delivery technique that uses positive infusion pressure to deliver therapeutic agents directly into the interstitial spaces of the brain. Despite the promise of CED, clinical trials have demonstrated that target-tissue anatomy and patient-specific physiology play a major role in drug distribution using this technique. In this study, we retrospectively tested the ability of a software algorithm using MR diffusion tensor imaging to predict patient-specific drug distributions by CED. A tumor-targeted cytotoxin, cintredekin besudotox (interleukin 13-PE38QQR), was coinfused with iodine 123-labeled human serum albumin (123I-HSA), in patients with recurrent malignant gliomas. The spatial distribution of 123I-HSA was then compared to a drug distribution simulation provided by the software algorithm. The algorithm had a high sensitivity (71.4%) and specificity (100%) for identifying the high proportion (7 of 14) of catheter trajectories that failed to deliver drug into the desired anatomical region (p = 0.021). This usually occurred when catheter trajectories crossed deep sulci, resulting in leak of the infusate into the subarachnoid cerebrospinal fluid space. The mean concordance of the volume of distribution at the 50% isodose level between the actual 123I-HSA distribution and simulation was 65.75% (95% confidence interval [CI], 52.0%-79.5%), and the mean maximal inplane deviation was less than 8.5 mm (95% CI, 4.0-13.0 mm). The use of this simulation algorithm was considered clinically useful in 84.6% of catheters. Routine use of this algorithm, and its further developments, should improve prospective selection of catheter trajectories, and thereby improve the efficacy of drugs delivered by this promising technique.

Authors
Sampson, JH; Raghavan, R; Brady, ML; Provenzale, JM; Herndon, JE; Croteau, D; Friedman, AH; Reardon, DA; Coleman, RE; Wong, T; Bigner, DD; Pastan, I; Rodríguez-Ponce, MI; Tanner, P; Puri, R; Pedain, C
MLA Citation
Sampson, JH, Raghavan, R, Brady, ML, Provenzale, JM, Herndon, JE, Croteau, D, Friedman, AH, Reardon, DA, Coleman, RE, Wong, T, Bigner, DD, Pastan, I, Rodríguez-Ponce, MI, Tanner, P, Puri, R, and Pedain, C. "Clinical utility of a patient-specific algorithm for simulating intracerebral drug infusions." Neuro Oncol 9.3 (July 2007): 343-353.
PMID
17435179
Source
pubmed
Published In
Neuro-Oncology
Volume
9
Issue
3
Publish Date
2007
Start Page
343
End Page
353
DOI
10.1215/15228517-2007-007

Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases.

Secreted protein acidic and rich in cysteine (SPARC) is an extracellular glycoprotein expressed in several solid cancers, including malignant gliomas, upon adoption of metastatic or invasive behaviors. SPARC expression in glioma cells promotes invasion and survival under stress, the latter process dependent on SPARC activation of AKT. Here we demonstrate that downregulation of SPARC expression with short interfering RNA (siRNA) in glioma cells decreased tumor cell survival and invasion. SPARC siRNA reduced the activating phosphorylation of AKT and two cytoplasmic kinases, focal adhesion kinase (FAK) and integrin-linked kinase (ILK). We determined the contributions of FAK and ILK to SPARC effects using SPARC protein and cell lines engineered to overexpress SPARC. SPARC activated FAK and ILK in glioma cells previously characterized as responsive to SPARC. Downregulation of either FAK or ILK expression inhibited SPARC-mediated AKT phosphorylation, and targeting both FAK and ILK attenuated AKT activation more potently than targeting either FAK or ILK alone. Decreased SPARC-mediated AKT activation correlated with a reduction in SPARC-dependent invasion and survival upon the downregulation of FAK and/or ILK expression. These data further demonstrate the role of SPARC in glioma tumor progression through the activation of intracellular kinases that may provide novel therapeutic targets for advanced cancers.

Authors
Shi, Q; Bao, S; Song, L; Wu, Q; Bigner, DD; Hjelmeland, AB; Rich, JN
MLA Citation
Shi, Q, Bao, S, Song, L, Wu, Q, Bigner, DD, Hjelmeland, AB, and Rich, JN. "Targeting SPARC expression decreases glioma cellular survival and invasion associated with reduced activities of FAK and ILK kinases." Oncogene 26.28 (June 14, 2007): 4084-4094.
PMID
17213807
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
26
Issue
28
Publish Date
2007
Start Page
4084
End Page
4094
DOI
10.1038/sj.onc.1210181

A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth.

Glioblastomas are highly lethal cancers that resist current therapies. Novel therapies under development target molecular mechanisms that promote glioblastoma growth. In glioblastoma patient specimens, the non-receptor tyrosine kinase focal adhesion kinase (FAK) is overexpressed. Upon growth factor receptor stimulation or integrin engagement, FAK is activated by phosphorylation on critical tyrosine residues. Activated FAK initiates a signal transduction cascade which promotes glioma growth and invasion by increasing cellular adhesion, migration, invasion, and proliferation. We find that human glioma cell lines express different levels of total FAK protein and activating phosphorylation of tyrosine residues Tyr397, Tyr861, and Tyr925. As all glioma cell lines examined expressed phosphorylated FAK, we examined the efficacy of a novel low-molecular weight inhibitor of FAK, TAE226, against human glioma cell lines. TAE226 inhibited the phosphorylation of FAK as well as the downstream effectors AKT, extracellular signal-related kinase, and S6 ribosomal protein in multiple glioma cell lines. TAE226 induced a concentration-dependent decrease in cellular proliferation with an associated G(2) cell cycle arrest in every cell line and an increase in apoptosis in a cell-line-specific manner. TAE226 also decreased glioma cell adhesion, migration, and invasion through an artificial extracellular matrix. Together, these data demonstrate the potential benefit of TAE226 for glioma therapy.

Authors
Shi, Q; Hjelmeland, AB; Keir, ST; Song, L; Wickman, S; Jackson, D; Ohmori, O; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Shi, Q, Hjelmeland, AB, Keir, ST, Song, L, Wickman, S, Jackson, D, Ohmori, O, Bigner, DD, Friedman, HS, and Rich, JN. "A novel low-molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth." Mol Carcinog 46.6 (June 2007): 488-496.
PMID
17219439
Source
pubmed
Published In
Molecular Carcinogenesis
Volume
46
Issue
6
Publish Date
2007
Start Page
488
End Page
496
DOI
10.1002/mc.20297

Tumor resection cavity administered iodine-131-labeled antitenascin 81C6 radioimmunotherapy in patients with malignant glioma: neuropathology aspects.

INTRODUCTION: The neurohistological findings in patients treated with targeted beta emitters such as (131)I are poorly described. We report a histopathologic analysis from patients treated with combined external beam therapy and a brachytherapy consisting of a (131)I-labeled monoclonal antibody (mAb) injected into surgically created resection cavities during brain tumor resections. METHODS: Directed tissue samples of the cavity walls were obtained because of suspected tumor recurrence from 28 patients. Samples and clinical follow-up were evaluated on all patients (Group A) based on total radiation dose received and a subset of these (n=18; Group B, proximal therapy subset) who had received external beam therapy within

Authors
McLendon, RE; Akabani, G; Friedman, HS; Reardon, DA; Cleveland, L; Cokgor, I; Herndon, JE; Wikstrand, C; Boulton, ST; Friedman, AH; Bigner, DD; Zalutsky, MR
MLA Citation
McLendon, RE, Akabani, G, Friedman, HS, Reardon, DA, Cleveland, L, Cokgor, I, Herndon, JE, Wikstrand, C, Boulton, ST, Friedman, AH, Bigner, DD, and Zalutsky, MR. "Tumor resection cavity administered iodine-131-labeled antitenascin 81C6 radioimmunotherapy in patients with malignant glioma: neuropathology aspects." Nucl Med Biol 34.4 (May 2007): 405-413.
PMID
17499730
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
34
Issue
4
Publish Date
2007
Start Page
405
End Page
413
DOI
10.1016/j.nucmedbio.2007.01.009

Antitenascin-C monoclonal antibody radioimmunotherapy for malignant glioma patients.

Adults with primary malignant glioma have an unacceptably poor outcome. Most of these tumors recur at or adjacent to the site of origin, which indicates that failure to eradicate local tumor growth is a major factor contributing to poor outcome. Therefore, locoregional therapies may improve local control and overall outcome for malignant glioma patients. Malignant gliomas selectively express several factors that are not present on normal CNS tissue. Regional administration of radiolabeled monoclonal antibodies targeting tumor-specific antigens expressed by malignant gliomas offers an innovative therapeutic strategy that has recently demonstrated encouraging antitumor activity and acceptable toxicity in clinical trials at a number of centers. Most studies have utilized monoclonal antibodies against tenascin-C, an extracellular matrix glycoprotein ubiquitously expressed by malignant gliomas. This review summarizes clinical trials performed using radiolabeled antitenascin-C monoclonal antibodies for malignant glioma patients to date and highlights future plans to further develop this therapeutic strategy.

Authors
Reardon, DA; Zalutsky, MR; Bigner, DD
MLA Citation
Reardon, DA, Zalutsky, MR, and Bigner, DD. "Antitenascin-C monoclonal antibody radioimmunotherapy for malignant glioma patients." Expert Rev Anticancer Ther 7.5 (May 2007): 675-687. (Review)
PMID
17492931
Source
pubmed
Published In
Expert Review of Anticancer Therapy
Volume
7
Issue
5
Publish Date
2007
Start Page
675
End Page
687
DOI
10.1586/14737140.7.5.675

Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function.

PURPOSE: Patients with malignant glioma suffer global compromise of their cellular immunity, characterized by dramatic reductions in CD4(+) T cell numbers and function. We have previously shown that increased regulatory T cell (T(reg)) fractions in these patients explain T-cell functional deficits. Our murine glioma model recapitulates these findings. Here, we investigate the effects of systemic CTLA-4 blockade in this model. EXPERIMENTAL DESIGN: A monoclonal antibody (9H10) to CTLA-4 was employed against well-established glioma. Survival and risks for experimental allergic encephalomyelitis were assessed, as were CD4(+) T cell numbers and function in the peripheral blood, spleen, and cervical lymph nodes. The specific capacities for anti-CTLA-4 to modify the functions of regulatory versus CD4(+)CD25(-) responder T cells were evaluated. RESULTS: CTLA-4 blockade confers long-term survival in 80% of treated mice, without eliciting experimental allergic encephalomyelitis. Changes to the CD4 compartment were reversed, as anti-CTLA-4 reestablishes normal CD4 counts and abrogates increases in CD4(+)CD25(+)Foxp3(+)GITR(+) regulatory T cell fraction observed in tumor-bearing mice. CD4(+) T-cell proliferative capacity is restored and the cervical lymph node antitumor response is enhanced. Treatment benefits are bestowed exclusively on the CD4(+)CD25(-) T cell population and not T(regs), as CD4(+)CD25(-) T cells from treated mice show improved proliferative responses and resistance to T(reg)-mediated suppression, whereas T(regs) from the same mice remain anergic and exhibit no restriction of their suppressive capacity. CONCLUSIONS: CTLA-4 blockade is a rational means of reversing glioma-induced changes to the CD4 compartment and enhancing antitumor immunity. These benefits were attained through the conferment of resistance to T(reg)-mediated suppression, and not through direct effects on T(regs).

Authors
Fecci, PE; Ochiai, H; Mitchell, DA; Grossi, PM; Sweeney, AE; Archer, GE; Cummings, T; Allison, JP; Bigner, DD; Sampson, JH
MLA Citation
Fecci, PE, Ochiai, H, Mitchell, DA, Grossi, PM, Sweeney, AE, Archer, GE, Cummings, T, Allison, JP, Bigner, DD, and Sampson, JH. "Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4+ T cell compartment without affecting regulatory T-cell function." Clin Cancer Res 13.7 (April 1, 2007): 2158-2167.
PMID
17404100
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
7
Publish Date
2007
Start Page
2158
End Page
2167
DOI
10.1158/1078-0432.CCR-06-2070

Using the theory of planned behavior to understand the determinants of exercise intention in patients diagnosed with primary brain cancer.

The purpose of the present study was to examine the demographic, medical, and social cognitive determinants of exercise intentions in a institution-based cohort of primary brain tumor patients. Using a cross-sectional survey, 100 primary brain tumor patients completed a mailed survey that assessed medical and demographic characteristics, past exercise behavior using the Godin Leisure Time Exercise Questionnaire (GLTEQ), and social cognitive beliefs towards exercise using Aizen's theory of planned behavior (TPB; i.e. intention, perceived behavioral control, subjective norm, affective and instrumental attitude). Descriptive statistics indicated that participants had positive social cognitive beliefs towards exercise. In support of the tenets of the TPB, we found moderate to large (>0.40) positive correlations between the majority of TPB constructs. Moreover, the TPB constructs combined to explain 32% of the variance in exercise intentions with affective attitude (beta = 0.24; p = 0.020) and perceived behavioral control (beta = 0.36; p<0.001) being the most important determinants. Except past exercise behavior, medical and demographic variables were not consistently correlated with any TPB constructs. Finally, participant's gender and body mass index influenced the association between instrumental attitude and exercise intention with male and overweight/obese patients (> or =25 kg/m(2)) considering the health benefits of exercise to be more important than their female and normal weight (<25 kg/m(2)) counterparts. Information gained from this study suggests that the TPB is a useful framework to design and implement theoretically based interventions to promote exercise in primary brain cancer patients.

Authors
Jones, LW; Guill, B; Keir, ST; Carter, K; Friedman, HS; Bigner, DD; Reardon, DA
MLA Citation
Jones, LW, Guill, B, Keir, ST, Carter, K, Friedman, HS, Bigner, DD, and Reardon, DA. "Using the theory of planned behavior to understand the determinants of exercise intention in patients diagnosed with primary brain cancer." Psychooncology 16.3 (March 2007): 232-240.
PMID
16929468
Source
pubmed
Published In
Psycho-Oncology
Volume
16
Issue
3
Publish Date
2007
Start Page
232
End Page
240
DOI
10.1002/pon.1077

Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma.

PURPOSE: Recurrent grade III-IV gliomas have a dismal prognosis with minimal improvements in survival seen following currently available salvage therapy. This study was conducted to determine if the combination of a novel antiangiogenic therapy, bevacizumab, and a cytotoxic agent, irinotecan, is safe and effective for patients with recurrent grade III-IV glioma. EXPERIMENTAL DESIGN: We conducted a phase II trial of bevacizumab and irinotecan in adults with recurrent grade III-IV glioma. Patients with evidence of intracranial hemorrhage on initial brain magnetic resonance imaging were excluded. Patients were scheduled to receive bevacizumab and irinotecan i.v. every 2 weeks of a 6-week cycle. Bevacizumab was administered at 10 mg/kg. The dose of irinotecan was determined based on antiepileptic use: patients taking enzyme-inducing antiepileptic drugs received 340 mg/m(2), whereas patients not taking enzyme-inducing antiepileptic drugs received 125 mg/m(2). Toxicity and response were assessed. RESULTS: Thirty-two patients were assessed (23 with grade IV glioma and 9 with grade III glioma). Radiographic responses were noted in 63% (20 of 32) of patients (14 of 23 grade IV patients and 6 of 9 grade III patients). The median progression-free survival was 23 weeks for all patients (95% confidence interval, 15-30 weeks; 20 weeks for grade IV patients and 30 weeks for grade III patients). The 6-month progression-free survival probability was 38% and the 6-month overall survival probability was 72%. No central nervous system hemorrhages occurred, but three patients developed deep venous thromboses or pulmonary emboli, and one patient had an arterial ischemic stroke. CONCLUSIONS: The combination of bevacizumab and irinotecan is an active regimen for recurrent grade III-IV glioma with acceptable toxicity.

Authors
Vredenburgh, JJ; Desjardins, A; Herndon, JE; Dowell, JM; Reardon, DA; Quinn, JA; Rich, JN; Sathornsumetee, S; Gururangan, S; Wagner, M; Bigner, DD; Friedman, AH; Friedman, HS
MLA Citation
Vredenburgh, JJ, Desjardins, A, Herndon, JE, Dowell, JM, Reardon, DA, Quinn, JA, Rich, JN, Sathornsumetee, S, Gururangan, S, Wagner, M, Bigner, DD, Friedman, AH, and Friedman, HS. "Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma." Clin Cancer Res 13.4 (February 15, 2007): 1253-1259.
PMID
17317837
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
13
Issue
4
Publish Date
2007
Start Page
1253
End Page
1259
DOI
10.1158/1078-0432.CCR-06-2309

Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: Descriptive effects of target anatomy and catheter positioning

OBJECTIVE: Convection-enhanced delivery (CED) holds tremendous potential for drug delivery to the brain. However, little is known about the volume of distribution achieved within human brain tissue or how target anatomy and catheter positioning influence drug distribution. The primary objective of this study was to quantitatively describe the distribution of a high molecular weight agent by CED relative to target anatomy and catheter position in patients with malignant gliomas. METHODS: Seven adult patients with recurrent malignant gliomas underwent intracerebral infusion of the tumor-targeted cytotoxin, cintredekin besudotox, concurrently with I-labeled human serum albumin. High-resolution single-photon emission computed tomographic images were obtained at 24 and 48 hours and were coregistered with magnetic resonance imaging scans. The distribution of I-labeled human serum albumin relative to target anatomy and catheter position was analyzed. RESULTS: Intracerebral CED infusions were well-tolerated and some resulted in a broad distribution of I-labeled human serum albumin, but target anatomy and catheter positioning had a significant influence on infusate distribution even within non-contrast-enhancing areas of brain. Intratumoral infusions were anisotropic and resulted in limited coverage of the enhancing tumor area and adjacent peritumoral regions. CONCLUSIONS: CED has the potential to deliver high molecular weight agents into tumor-infiltrated brain parenchyma with volumes of distribution that are clinically relevant. Target tissue anatomy and catheter position are critical parameters in optimizing drug delivery. Copyright © by the Congress of Neurological Surgeons.

Authors
Sampson, JH; Brady, ML; Petry, NA; Croteau, D; Friedman, AH; Friedman, HS; Wong, T; Bigner, DD; Pastan, I; Puri, RK; Pedain, C
MLA Citation
Sampson, JH, Brady, ML, Petry, NA, Croteau, D, Friedman, AH, Friedman, HS, Wong, T, Bigner, DD, Pastan, I, Puri, RK, and Pedain, C. "Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: Descriptive effects of target anatomy and catheter positioning." Neurosurgery 60.2 SUPPL.1 (February 1, 2007).
Source
scopus
Published In
Neurosurgery
Volume
60
Issue
2 SUPPL.1
Publish Date
2007
DOI
10.1227/01.NEU.0000249256.09289.5F

Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: descriptive effects of target anatomy and catheter positioning.

OBJECTIVE: Convection-enhanced delivery (CED) holds tremendous potential for drug delivery to the brain. However, little is known about the volume of distribution achieved within human brain tissue or how target anatomy and catheter positioning influence drug distribution. The primary objective of this study was to quantitatively describe the distribution of a high molecular weight agent by CED relative to target anatomy and catheter position in patients with malignant gliomas. METHODS: Seven adult patients with recurrent malignant gliomas underwent intracerebral infusion of the tumor-targeted cytotoxin, cintredekin besudotox, concurrently with 123I-labeled human serum albumin. High-resolution single-photon emission computed tomographic images were obtained at 24 and 48 hours and were coregistered with magnetic resonance imaging scans. The distribution of 123I-labeled human serum albumin relative to target anatomy and catheter position was analyzed. RESULTS: Intracerebral CED infusions were well-tolerated and some resulted in a broad distribution of 123I-labeled human serum albumin, but target anatomy and catheter positioning had a significant influence on infusate distribution even within non-contrast-enhancing areas of brain. Intratumoral infusions were anisotropic and resulted in limited coverage of the enhancing tumor area and adjacent peritumoral regions. CONCLUSIONS: CED has the potential to deliver high molecular weight agents into tumor-infiltrated brain parenchyma with volumes of distribution that are clinically relevant. Target tissue anatomy and catheter position are critical parameters in optimizing drug delivery.

Authors
Sampson, JH; Brady, ML; Petry, NA; Croteau, D; Friedman, AH; Friedman, HS; Wong, T; Bigner, DD; Pastan, I; Puri, RK; Pedain, C
MLA Citation
Sampson, JH, Brady, ML, Petry, NA, Croteau, D, Friedman, AH, Friedman, HS, Wong, T, Bigner, DD, Pastan, I, Puri, RK, and Pedain, C. "Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: descriptive effects of target anatomy and catheter positioning." Neurosurgery 60.2 Suppl 1 (February 2007): ONS89-ONS98.
PMID
17297371
Source
pubmed
Published In
Neurosurgery
Volume
60
Issue
2 Suppl 1
Publish Date
2007
Start Page
ONS89
End Page
ONS98
DOI
10.1227/01.NEU.0000249256.09289.5F

Antitenascin antibody 81C6 armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands.

INTRODUCTION: When labeled with iodine-131, the antitenascin monoclonal antibody (mAb) 81C6 has shown promise as a targeted radiotherapeutic in patients with brain tumors. Because of its more favorable gamma-ray properties, lutetium-177 might be a better low-energy beta-emitter for this type of therapy. MATERIALS AND METHODS: Chimeric 81C6 (ch81C6) was labeled with (177)Lu using the acyclic 1B4M ligand and the macrocyclic ligands NHS-DOTA and MeO-DOTA and evaluated for binding to tenascin. Three paired-label tissue distribution experiments were performed in normal mice receiving one of the (177)Lu-labeled immunoconjugates plus (125)I-labeled ch81C6 labeled using Iodogen. Paired-label experiments in athymic mice bearing subcutaneous D54 MG human glioma xenografts were done to directly compare the biodistribution of ch81C6-1B4M-(177)Lu and (125)I-labeled ch81C6, and ch81C6-MeO-DOTA-(177)Lu and (125)I-labeled ch81C6. Similar comparisons were done using murine (mu) instead of ch81C6. The primary parameter utilized for evaluation was the (177)Lu/(125)I uptake ratio in each tissue. RESULTS: In the studies performed in normal mice, the NHS-DOTA ligand yielded the highest (177)Lu/(125)I uptake ratios in tissues indicative of loss of label from the chelate; for this reason, only 1B4M and MeO-DOTA were evaluated further. The (177)Lu/(125)I ratio in bone increased gradually with time for the chimeric conjugates; however, there were no significant differences between ch81C6-1B4M-DTPA-(177)Lu and ch81C6-MeO-DOTA-(177)Lu. In contrast, mu81C6-1B4M-DTPA-(177)Lu and mu81C6-MeO-DOTA-(177)Lu showed a more dramatic increase in the (177)Lu/(125)I ratio in bone - from 2.4+/-0.3 and 1.7+/-0.2 at Day 1 to 8.5+/-1.1 and 4.2+/-0.5 at Day 7, respectively. CONCLUSION: With these antitenascin constructs, the nature of the mAb had a profound influence on the relative degree of loss of (177)Lu from these immunoconjugates. MeO-DOTA shows promise as a bifunctional chelate for labeling 81C6 mAbs with (177)Lu.

Authors
Yordanov, AT; Hens, M; Pegram, C; Bigner, DD; Zalutsky, MR
MLA Citation
Yordanov, AT, Hens, M, Pegram, C, Bigner, DD, and Zalutsky, MR. "Antitenascin antibody 81C6 armed with 177Lu: in vivo comparison of macrocyclic and acyclic ligands." Nucl Med Biol 34.2 (February 2007): 173-183.
PMID
17307125
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
34
Issue
2
Publish Date
2007
Start Page
173
End Page
183
DOI
10.1016/j.nucmedbio.2006.11.003

Phase II study of Cloretazine for the treatment of adults with recurrent glioblastoma multiforme.

Cloretazine (VNP40101M) is a newly synthesized alkylating agent belonging to a novel class of alkylating agents called 1,2-bis(sulfonyl)hydrazines. Agents that belong to this class do not produce vinylating and chloroethylating species, and hence this class of alkylating agents is thought to have minimal systemic toxicity. Cloretazine produces two short-lived active species: 1,2-bis(methylsulfonyl)-1-(2-chloroethyl) hydrazine (a chloroethylating species) and a thiophilic carbamoylating methylisocyanate species. The chloroethylating species preferentially produces lesions at the O(6) position of guanine. The methylisocyanate species may inhibit O(6)-alkylguanine-DNA alkyltransferase, an important mechanism of resistance against alkylating agents. The purpose of this study was to determine the efficacy and tolerability of Cloretazine in patients with recurrent glioblastoma multiforme. The basis for the determination of efficacy was the proportion of patients alive without evidence of disease progression six months after initiation of treatment. Patients with recurrent glioblastoma multiforme received Cloretazine (300 mg/m(2)) intravenously every six weeks. Radiographic response, survival data, and toxicity were assessed. Thirty-two patients were enrolled. Median age was 56 years; 24 patients (75%) were men. At six months, two patients were alive and progression free, so the six-month progression-free survival (PFS) was 6%. The median PFS was 6.3 weeks. There were no objective radiographic responses. Twelve patients had stable disease for at least one cycle, but only two patients received more than three cycles. Nine patients experienced grade 4 thrombocytopenia and three patients experienced grade 4 neutropenia. Cloretazine administered every six weeks was relatively well tolerated, although this schedule has insignificant activity for patients with recurrent glioblastoma multiforme.

Authors
Badruddoja, MA; Penne, K; Desjardins, A; Reardon, DA; Rich, JN; Quinn, JA; Sathornsumetee, S; Friedman, AH; Bigner, DD; Herndon, JE; Cahill, A; Friedman, HS; Vredenburgh, JJ
MLA Citation
Badruddoja, MA, Penne, K, Desjardins, A, Reardon, DA, Rich, JN, Quinn, JA, Sathornsumetee, S, Friedman, AH, Bigner, DD, Herndon, JE, Cahill, A, Friedman, HS, and Vredenburgh, JJ. "Phase II study of Cloretazine for the treatment of adults with recurrent glioblastoma multiforme." Neuro Oncol 9.1 (January 2007): 70-74.
PMID
17108065
Source
pubmed
Published In
Neuro-Oncology
Volume
9
Issue
1
Publish Date
2007
Start Page
70
End Page
74
DOI
10.1215/15228517-2006-022

Exercise interest and preferences among patients diagnosed with primary brain cancer.

GOALS OF THE WORK: The purpose of the present investigation was to examine the interest and exercise preferences of an institution-based sample of brain tumor patients. Secondary aims were to examine potential differences in participant's interest and preferences by exercise behavior and select demographic/medical variables. MATERIALS AND METHODS: Using a cross-sectional design, 106 brain tumor patients (age range, 32 to 83 years) who received treatment at the Preston Robert Tisch Brain Tumor Center (BTC) at Duke completed a questionnaire that assessed self-reported exercise behavior, exercise interest and preferences during active and off-treatment periods. MAIN RESULTS: For exercise program preferences, participants were significantly more interested and felt more capable of participating in an exercise program following compared to during adjuvant therapy. Approximately equal proportions of brain tumor patients preferred to exercise at home with their spouse or other family members. These preferences were consistent across both cancer treatment-related time periods. For exercise information preferences, a higher proportion of respondents preferred receiving information via technologically based approaches (i.e., Internet, CD-ROM, and mailed correspondence) compared with more traditional methods (i.e., mail or face-to-face counseling). Chi-square analyses revealed that a small number of exercise program and information preferences were modified by exercise, medical, and demographic variables. CONCLUSIONS: Brain tumor patients may have unique and varied preferences compared with other cancer populations. Incorporating patient's preferences into rehabilitation programs and clinical exercise investigations may optimize the potential benefits of this modality for patients with neurologic malignancies.

Authors
Jones, LW; Guill, B; Keir, ST; Carter, K; Friedman, HS; Bigner, DD; Reardon, DA
MLA Citation
Jones, LW, Guill, B, Keir, ST, Carter, K, Friedman, HS, Bigner, DD, and Reardon, DA. "Exercise interest and preferences among patients diagnosed with primary brain cancer." Support Care Cancer 15.1 (January 2007): 47-55.
PMID
16819629
Source
pubmed
Published In
Supportive Care in Cancer
Volume
15
Issue
1
Publish Date
2007
Start Page
47
End Page
55
DOI
10.1007/s00520-006-0096-8

Glioma stem cells promote radioresistance by preferential activation of the DNA damage response.

Ionizing radiation represents the most effective therapy for glioblastoma (World Health Organization grade IV glioma), one of the most lethal human malignancies, but radiotherapy remains only palliative because of radioresistance. The mechanisms underlying tumour radioresistance have remained elusive. Here we show that cancer stem cells contribute to glioma radioresistance through preferential activation of the DNA damage checkpoint response and an increase in DNA repair capacity. The fraction of tumour cells expressing CD133 (Prominin-1), a marker for both neural stem cells and brain cancer stem cells, is enriched after radiation in gliomas. In both cell culture and the brains of immunocompromised mice, CD133-expressing glioma cells survive ionizing radiation in increased proportions relative to most tumour cells, which lack CD133. CD133-expressing tumour cells isolated from both human glioma xenografts and primary patient glioblastoma specimens preferentially activate the DNA damage checkpoint in response to radiation, and repair radiation-induced DNA damage more effectively than CD133-negative tumour cells. In addition, the radioresistance of CD133-positive glioma stem cells can be reversed with a specific inhibitor of the Chk1 and Chk2 checkpoint kinases. Our results suggest that CD133-positive tumour cells represent the cellular population that confers glioma radioresistance and could be the source of tumour recurrence after radiation. Targeting DNA damage checkpoint response in cancer stem cells may overcome this radioresistance and provide a therapeutic model for malignant brain cancers.

Authors
Bao, S; Wu, Q; McLendon, RE; Hao, Y; Shi, Q; Hjelmeland, AB; Dewhirst, MW; Bigner, DD; Rich, JN
MLA Citation
Bao, S, Wu, Q, McLendon, RE, Hao, Y, Shi, Q, Hjelmeland, AB, Dewhirst, MW, Bigner, DD, and Rich, JN. "Glioma stem cells promote radioresistance by preferential activation of the DNA damage response." Nature 444.7120 (December 7, 2006): 756-760.
PMID
17051156
Source
pubmed
Published In
Nature
Volume
444
Issue
7120
Publish Date
2006
Start Page
756
End Page
760
DOI
10.1038/nature05236

Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma.

Promoter hypermethylation of the DNA repair protein O(6)-alkylguanine-DNA alkyltransferase (AGT) has been associated with an enhanced response to chloroethylating and methylating agents in patients with malignant glioma. The purpose of this study was to compare three distinct yet related indices for measuring AGT to determine if these assays could be used interchangeably when AGT status is to be used to guide chemotherapeutic decisions. Real-time methylation-specific PCR (MSP), assessed as the ratio of methylated AGT copies to internal beta-actin control, was used to quantitate AGT hypermethylation in 32 glioma samples. Data were compared with AGT enzyme activity as well as immunohistochemical detection of AGT protein from the same samples. Hypermethylation of the AGT promoter was detected in 19 of 31 (61%) samples evaluable by MSP. Low-level AGT, defined as <20% nuclear AGT staining by immunohistochemistry, was found in 10 of 32 samples (31%), whereas 12 of 32 (38%) had low levels of AGT activity. Correlation of immunohistochemistry to AGT activity was statistically significant (P = 0.014) as was the correlation of immunohistochemistry to MSP (P = 0.043), whereas MSP compared with AGT activity (P = 0.246) was not significant. Cross-tabulation of immunohistochemistry and MSP data based on prognostic groups, where good prognosis was represented by an immunohistochemistry of <20% and an MSP ratio >12, showed no significant relationship (P = 0.214), suggesting that one assay cannot be used interchangeably for another. The observed discordance between respective measures of AGT based on prognosis supports further standardization of AGT assays designed to guide therapeutic practice. The data also suggest that consideration be given to the large population of AGT-expressing cells within samples when therapeutic strategies based on tumor methylation are used.

Authors
Maxwell, JA; Johnson, SP; Quinn, JA; McLendon, RE; Ali-Osman, F; Friedman, AH; Herndon, JE; Bierau, K; Bigley, J; Bigner, DD; Friedman, HS
MLA Citation
Maxwell, JA, Johnson, SP, Quinn, JA, McLendon, RE, Ali-Osman, F, Friedman, AH, Herndon, JE, Bierau, K, Bigley, J, Bigner, DD, and Friedman, HS. "Quantitative analysis of O6-alkylguanine-DNA alkyltransferase in malignant glioma." Mol Cancer Ther 5.10 (October 2006): 2531-2539.
PMID
17041097
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
5
Issue
10
Publish Date
2006
Start Page
2531
End Page
2539
DOI
10.1158/1535-7163.MCT-06-0106

AAL881, a novel small molecule inhibitor of RAF and VEGFR activities, blocks growth of malignant glioma

Authors
Sathornsumetee, S; Hjelmeland, AB; Keir, ST; McLendon, RE; Batt, D; Ramsey, T; Yusuff, N; Ahmed Rasheed, BK; Kieran, MW; Laforme, A; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Sathornsumetee, S, Hjelmeland, AB, Keir, ST, McLendon, RE, Batt, D, Ramsey, T, Yusuff, N, Ahmed Rasheed, BK, Kieran, MW, Laforme, A, Bigner, DD, Friedman, HS, and Rich, JN. "AAL881, a novel small molecule inhibitor of RAF and VEGFR activities, blocks growth of malignant glioma." October 2006.
Source
wos-lite
Published In
Neuro-Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
417
End Page
417

Glioma cancer stem cells promote tumor angiogenesis through vascular endothelial growth factor

Authors
Bao, S; Wu, Q; Sathornsumetee, S; Hao, Y; Li, Z; Hjelmeland, AB; Shi, Q; McLendon, RE; Bigner, DD; Rich, JN
MLA Citation
Bao, S, Wu, Q, Sathornsumetee, S, Hao, Y, Li, Z, Hjelmeland, AB, Shi, Q, McLendon, RE, Bigner, DD, and Rich, JN. "Glioma cancer stem cells promote tumor angiogenesis through vascular endothelial growth factor." October 2006.
Source
wos-lite
Published In
Neuro-Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
392
End Page
392

Characterizing genomic rearrangements in oligodendroglioma using whole genome tilepath hrCGH arrays

Authors
Gregory, SG; Johnson, NV; Connelly, JJ; Virgadamo, J; McLendon, RE; Vance, JM; Bigner, DD
MLA Citation
Gregory, SG, Johnson, NV, Connelly, JJ, Virgadamo, J, McLendon, RE, Vance, JM, and Bigner, DD. "Characterizing genomic rearrangements in oligodendroglioma using whole genome tilepath hrCGH arrays." October 2006.
Source
wos-lite
Published In
Neuro-Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
421
End Page
421

Bevacizumab and irinotecan is an effective treatment for malignant gliomas

Authors
Vredenburgh, J; Desjardins, A; II, HJE; Reardon, D; Quinn, J; Sathornsumetee, S; Gururangan, S; Friedman, A; Bigner, D; Friedman, H
MLA Citation
Vredenburgh, J, Desjardins, A, II, HJE, Reardon, D, Quinn, J, Sathornsumetee, S, Gururangan, S, Friedman, A, Bigner, D, and Friedman, H. "Bevacizumab and irinotecan is an effective treatment for malignant gliomas." October 2006.
Source
wos-lite
Published In
Neuro-Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
454
End Page
454

Glutathione S-transferase P1 (GSTP1) is a novel downstream target of Akt in human gliomas

Authors
Okamura, T; Haystead, T; Bigner, DD; Ali-Osman, F
MLA Citation
Okamura, T, Haystead, T, Bigner, DD, and Ali-Osman, F. "Glutathione S-transferase P1 (GSTP1) is a novel downstream target of Akt in human gliomas." October 2006.
Source
wos-lite
Published In
Neuro-Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
400
End Page
400

Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting.

PURPOSE: Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where expression levels correlate with decreased survival. Therapies that block EGFR have shown limited efficacy in clinical trials and primarily when combined with standard therapy. The most common form of mutant EGFR (EGFRvIII) has been described in several cancers, chiefly glioblastoma. The present study was undertaken to determine the incidence of EGFRvIII expression in HNSCC and the biological consequences of EGFRvIII on tumor growth in response to EGFR targeting. EXPERIMENTAL DESIGN: Thirty-three HNSCC tumors were evaluated by immunostaining and reverse transcription-PCR for EGFRvIII expression. A representative HNSCC cell line was stably transfected with an EGFRvIII expression construct. EGFRvIII-expressing cells and vector-transfected controls were compared for growth rates in vitro and in vivo as well as chemotherapy-induced apoptosis and the consequences of EGFR inhibition using the chimeric monoclonal antibody C225/cetuximab/Erbitux. RESULTS: EGFRvIII expression was detected in 42% of HNSCC tumors where EGFRvIII was always found in conjunction with wild-type EGFR. HNSCC cells expressing EGFRvIII showed increased proliferation in vitro and increased tumor volumes in vivo compared with vector-transfected controls. Furthermore, EGFRvIII-transfected HNSCC cells showed decreased apoptosis in response to cisplatin and decreased growth inhibition following treatment with C225 compared with vector-transfected control cells. CONCLUSIONS: EGFRvIII is expressed in HNSCC where it contributes to enhanced growth and resistance to targeting wild-type EGFR. The antitumor efficacy of EGFR targeting strategies may be enhanced by the addition of EGFRvIII-specific blockade.

Authors
Sok, JC; Coppelli, FM; Thomas, SM; Lango, MN; Xi, S; Hunt, JL; Freilino, ML; Graner, MW; Wikstrand, CJ; Bigner, DD; Gooding, WE; Furnari, FB; Grandis, JR
MLA Citation
Sok, JC, Coppelli, FM, Thomas, SM, Lango, MN, Xi, S, Hunt, JL, Freilino, ML, Graner, MW, Wikstrand, CJ, Bigner, DD, Gooding, WE, Furnari, FB, and Grandis, JR. "Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting." Clin Cancer Res 12.17 (September 1, 2006): 5064-5073.
PMID
16951222
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
17
Publish Date
2006
Start Page
5064
End Page
5073
DOI
10.1158/1078-0432.CCR-06-0913

AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma.

Malignant gliomas are highly proliferative and angiogenic cancers resistant to conventional therapies. Although RAS and RAF mutations are uncommon in gliomas, RAS activity is increased in gliomas. Additionally, vascular endothelial growth factor and its cognate receptors are highly expressed in gliomas. We now report that AAL881, a novel low-molecular weight inhibitor of the kinase activities associated with B-RAF, C-RAF (RAF-1), and VEGF receptor-2 (VEGFR2), showed activity against glioma cell lines and xenografts. In culture, AAL881 inhibited the downstream effectors of RAF in a concentration-dependent manner, with inhibition of proliferation associated with a G(1) cell cycle arrest, induction of apoptosis, and decreased colony formation. AAL881 decreased the proliferation of bovine aortic endothelial cells as well as the tumor cell secretion of vascular endothelial growth factor and inhibited the invasion of glioma cells through an artificial extracellular matrix. Orally administered AAL881 was well tolerated with minimal weight loss in non-tumor-bearing mice. Established s.c. human malignant glioma xenografts grown in immunocompromised mice treated with a 10-day course of oral AAL881 exhibited growth delays relative to control tumors, frequently resulting in long-term complete regressions. AAL881 treatment extended the survival of immunocompromised mice bearing orthotopic glioma xenografts compared with placebo controls. The intraparenchymal portions of orthotopic AAL881-treated tumors underwent widespread necrosis consistent with vascular disruption compared with the subarachnoid elements. These effects are distinct from our prior experience with VEGFR2 inhibitors, suggesting that targeting RAF itself or in combination with VEGFR2 induces profound tumor responses in gliomas and may serve as a novel therapeutic approach in patients with malignant gliomas.

Authors
Sathornsumetee, S; Hjelmeland, AB; Keir, ST; McLendon, RE; Batt, D; Ramsey, T; Yusuff, N; Rasheed, BKA; Kieran, MW; Laforme, A; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Sathornsumetee, S, Hjelmeland, AB, Keir, ST, McLendon, RE, Batt, D, Ramsey, T, Yusuff, N, Rasheed, BKA, Kieran, MW, Laforme, A, Bigner, DD, Friedman, HS, and Rich, JN. "AAL881, a novel small molecule inhibitor of RAF and vascular endothelial growth factor receptor activities, blocks the growth of malignant glioma." Cancer Res 66.17 (September 1, 2006): 8722-8730.
PMID
16951188
Source
pubmed
Published In
Cancer Research
Volume
66
Issue
17
Publish Date
2006
Start Page
8722
End Page
8730
DOI
10.1158/0008-5472.CAN-06-0284

At-211-labeled trastuzumab: Evaluation of an alpha-particle emitting targeted radiotherapeutic for the treatment of breast carcinoma carcinomatous meningitis

Authors
Boskovitz, A; Ochiai, H; Okamura, T; Akabani, G; Carlin, S; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, Ochiai, H, Okamura, T, Akabani, G, Carlin, S, Bigner, DD, and Zalutsky, MR. "At-211-labeled trastuzumab: Evaluation of an alpha-particle emitting targeted radiotherapeutic for the treatment of breast carcinoma carcinomatous meningitis." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 (September 2006): S184-S184.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S184
End Page
S184

Chimeric murine/human IgG(2) anti-tenascin 81C6 monoclonal antibody: phase I trial in patients with malignant glioma of a construct with improved stability

Authors
Zalutsky, MR; Reardon, DA; Quinn, JA; Coleman, RE; Akabani, G; Friedman, AH; Friedman, HS; II, HJE; McLendon, RE; Wong, TZ; Bigner, DD
MLA Citation
Zalutsky, MR, Reardon, DA, Quinn, JA, Coleman, RE, Akabani, G, Friedman, AH, Friedman, HS, II, HJE, McLendon, RE, Wong, TZ, and Bigner, DD. "Chimeric murine/human IgG(2) anti-tenascin 81C6 monoclonal antibody: phase I trial in patients with malignant glioma of a construct with improved stability." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 (September 2006): S194-S194.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S194
End Page
S194

At-211-labeled trastuzumab: Evaluation of an alpha-particle emitting targeted radiotherapeutic for the treatment of breast carcinoma carcinomatous meningitis

Authors
Boskovitz, A; Ochiai, H; Okamura, T; Akabani, G; Carlin, S; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, Ochiai, H, Okamura, T, Akabani, G, Carlin, S, Bigner, DD, and Zalutsky, MR. "At-211-labeled trastuzumab: Evaluation of an alpha-particle emitting targeted radiotherapeutic for the treatment of breast carcinoma carcinomatous meningitis." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 (September 2006): S378-S378.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S378
End Page
S378

Radioimmunotherapy of patients with malignant brain tumors: patient-specific dosing of I-131-labeled anti-tenacin antibody to achieve 44 Gy boost dose to resection cavity margins

Authors
Reardon, DA; Zalutsky, MR; Akabani, G; Coleman, RE; Friedman, AH; McLendon, RE; Friedman, HS; II, HJE; Kirkpatrick, J; Bigner, DD
MLA Citation
Reardon, DA, Zalutsky, MR, Akabani, G, Coleman, RE, Friedman, AH, McLendon, RE, Friedman, HS, II, HJE, Kirkpatrick, J, and Bigner, DD. "Radioimmunotherapy of patients with malignant brain tumors: patient-specific dosing of I-131-labeled anti-tenacin antibody to achieve 44 Gy boost dose to resection cavity margins." EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING 33 (September 2006): S194-S194.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
33
Publish Date
2006
Start Page
S194
End Page
S194

Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor.

Malignant gliomas are highly lethal cancers dependent on angiogenesis. Critical tumor subpopulations within gliomas share characteristics with neural stem cells. We examined the potential of stem cell-like glioma cells (SCLGC) to support tumor angiogenesis. SCLGC isolated from human glioblastoma biopsy specimens and xenografts potently generated tumors when implanted into the brains of immunocompromised mice, whereas non-SCLGC tumor cells isolated from only a few tumors formed secondary tumors when xenotransplanted. Tumors derived from SCLGC were morphologically distinguishable from non-SCLGC tumor populations by widespread tumor angiogenesis, necrosis, and hemorrhage. To determine a potential molecular mechanism for SCLGC in angiogenesis, we measured the expression of a panel of angiogenic factors secreted by SCLGC. In comparison with matched non-SCLGC populations, SCLGC consistently secreted markedly elevated levels of vascular endothelial growth factor (VEGF), which were further induced by hypoxia. In an in vitro model of angiogenesis, SCLGC-conditioned medium significantly increased endothelial cell migration and tube formation compared with non-SCLGC tumor cell-conditioned medium. The proangiogenic effects of glioma SCLGC on endothelial cells were specifically abolished by the anti-VEGF neutralizing antibody bevacizumab, which is in clinical use for cancer therapy. Furthermore, bevacizumab displayed potent antiangiogenic efficacy in vivo and suppressed growth of xenografts derived from SCLGC but limited efficacy against xenografts derived from a matched non-SCLGC population. Together these data indicate that stem cell-like tumor cells can be a crucial source of key angiogenic factors in cancers and that targeting proangiogenic factors from stem cell-like tumor populations may be critical for patient therapy.

Authors
Bao, S; Wu, Q; Sathornsumetee, S; Hao, Y; Li, Z; Hjelmeland, AB; Shi, Q; McLendon, RE; Bigner, DD; Rich, JN
MLA Citation
Bao, S, Wu, Q, Sathornsumetee, S, Hao, Y, Li, Z, Hjelmeland, AB, Shi, Q, McLendon, RE, Bigner, DD, and Rich, JN. "Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor." Cancer Res 66.16 (August 15, 2006): 7843-7848.
PMID
16912155
Source
pubmed
Published In
Cancer Research
Volume
66
Issue
16
Publish Date
2006
Start Page
7843
End Page
7848
DOI
10.1158/0008-5472.CAN-06-1010

Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells.

PURPOSE: Elevated proportions of regulatory T cells (T(reg)) are present in patients with a variety of cancers, including malignant glioma, yet recapitulative murine models are wanting. We therefore examined T(regs) in mice bearing malignant glioma and evaluated anti-CD25 as an immunotherapeutic adjunct. EXPERIMENTAL DESIGN: CD4+CD25+Foxp3+GITR+ T(regs) were quantified in the peripheral blood, spleens, cervical lymph nodes, and bone marrow of mice bearing malignant glioma. The capacities for systemic anti-CD25 therapy to deplete T(regs), enhance lymphocyte function, and generate antiglioma CTL responses were assessed. Lastly, survival and experimental allergic encephalitis risks were evaluated when anti-CD25 was combined with a dendritic cell-based immunization targeting shared tumor and central nervous system antigens. RESULTS: Similar to patients with malignant glioma, glioma-bearing mice show a CD4 lymphopenia. Additionally, CD4+CD25+Foxp3+GITR+ T(regs) represent an increased fraction of the remaining peripheral blood CD4+ T cells, despite themselves being reduced in number. Similar trends are observed in cervical lymph node and spleen, but not in bone marrow. Systemic anti-CD25 administration hinders detection of CD25+ cells but fails to completely eliminate T(regs), reducing their number only moderately, yet eliminating their suppressive function. This elimination of T(reg) function permits enhanced lymphocyte proliferative and IFN-gamma responses and up to 80% specific lysis of glioma cell targets in vitro. When combined with dendritic cell immunization, anti-CD25 elicits tumor rejection in 100% of challenged mice without precipitating experimental allergic encephalitis. CONCLUSIONS: Systemic anti-CD25 administration does not entirely eliminate T(regs) but does prevent T(reg) function. This leads to safe enhancement of tumor immunity in a murine glioma model that recapitulates the tumor-induced changes to the CD4 and T(reg) compartments seen in patients with malignant glioma.

Authors
Fecci, PE; Sweeney, AE; Grossi, PM; Nair, SK; Learn, CA; Mitchell, DA; Cui, X; Cummings, TJ; Bigner, DD; Gilboa, E; Sampson, JH
MLA Citation
Fecci, PE, Sweeney, AE, Grossi, PM, Nair, SK, Learn, CA, Mitchell, DA, Cui, X, Cummings, TJ, Bigner, DD, Gilboa, E, and Sampson, JH. "Systemic anti-CD25 monoclonal antibody administration safely enhances immunity in murine glioma without eliminating regulatory T cells." Clin Cancer Res 12.14 Pt 1 (July 15, 2006): 4294-4305.
PMID
16857805
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
14 Pt 1
Publish Date
2006
Start Page
4294
End Page
4305
DOI
10.1158/1078-0432.CCR-06-0053

Nε-(3[*I]iodobenzoyl)-Lys5-N α-maleimido-Gly1-GEEEK([*I]IB-Mal-D-GEEEK): A radioiodinated prosthetic group containing negatively charged D-glutamates for labeling internalizing monoclonal antibodies

Novel methods are needed for the radiohalogenation of cell-internalizing proteins and peptides because rapid loss of label occurs after lysosomal processing when these molecules are labeled using conventional radioiodination methodologies. We have developed a radiolabeled prosthetic group that contains multiple negatively charged D-amino acids to facilitate trapping of the radioactivity in the cell after proteolysis of the labeled protein. N ε-(3-[125I]iodobenzoyl-Lys5-N α-maleimido-Gly1-GEEEK ([125I]IB-Mal-D- GEEEK) was synthesized via iododestannylation in 90.3 ± 3.9% radiochemical yields. This radioiodinated agent was conjugated to iminothiolane-treated L8A4, an anti-epidermal growth factor receptor variant III (EGFRvIII) specific monoclonal antibody (mAb) in 54.3 ± 17.7% conjugation yields. In vitro assays with the EGFRvIII-expressing U87MGΔEGFR glioma cell line demonstrated that the internalized radioactivity for the [125I]IB-Mal-D-GEEEK-L8A4 conjugate increased from 14.1% at 1 h to 44.7% at 24 h and was about 15-fold higher than that of directly radioiodinated L8A4 at 24 h. A commensurately increased tumor uptake in vivo in athymic mice bearing subcutaneous U87MGΔEGFR xenografts (52.6 ± 14.3% injected dose per gram versus 17.4 ± 3.5% ID/g at 72 h) also was observed. These results suggest that [125I]IB-Mal-D-GEEEK is a promising reagent for the radioiodination of internalizing mAbs. © 2006 American Chemical Society.

Authors
Vaidyanathan, G; Alston, KL; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Alston, KL, Bigner, DD, and Zalutsky, MR. "Nε-(3[*I]iodobenzoyl)-Lys5-N α-maleimido-Gly1-GEEEK([*I]IB-Mal-D-GEEEK): A radioiodinated prosthetic group containing negatively charged D-glutamates for labeling internalizing monoclonal antibodies." Bioconjugate Chemistry 17.4 (July 1, 2006): 1085-1092.
Source
scopus
Published In
Bioconjugate Chemistry
Volume
17
Issue
4
Publish Date
2006
Start Page
1085
End Page
1092
DOI
10.1021/bc0600766

Nepsilon-(3-[*I]Iodobenzoyl)-Lys5-Nalpha-maleimido-Gly1-GEEEK ([*I]IB-Mal-D-GEEEK): a radioiodinated prosthetic group containing negatively charged D-glutamates for labeling internalizing monoclonal antibodies.

Novel methods are needed for the radiohalogenation of cell-internalizing proteins and peptides because rapid loss of label occurs after lysosomal processing when these molecules are labeled using conventional radioiodination methodologies. We have developed a radiolabeled prosthetic group that contains multiple negatively charged D-amino acids to facilitate trapping of the radioactivity in the cell after proteolysis of the labeled protein. N(epsilon)-(3-[(125)I]iodobenzoyl)-Lys(5)-N(alpha)-maleimido-Gly(1)-GEEEK ([(125)I]IB-Mal-D-GEEEK) was synthesized via iododestannylation in 90.3 +/- 3.9% radiochemical yields. This radioiodinated agent was conjugated to iminothiolane-treated L8A4, an anti-epidermal growth factor receptor variant III (EGFRvIII) specific monoclonal antibody (mAb) in 54.3 +/- 17.7% conjugation yields. In vitro assays with the EGFRvIII-expressing U87MGDeltaEGFR glioma cell line demonstrated that the internalized radioactivity for the [(125)I]IB-Mal-D-GEEEK-L8A4 conjugate increased from 14.1% at 1 h to 44.7% at 24 h and was about 15-fold higher than that of directly radioiodinated L8A4 at 24 h. A commensurately increased tumor uptake in vivo in athymic mice bearing subcutaneous U87MGDeltaEGFR xenografts (52.6 +/- 14.3% injected dose per gram versus 17.4 +/- 3.5% ID/g at 72 h) also was observed. These results suggest that [(125)I]IB-Mal-d-GEEEK is a promising reagent for the radioiodination of internalizing mAbs.

Authors
Vaidyanathan, G; Alston, KL; Bigner, DD; Zalutsky, MR
MLA Citation
Vaidyanathan, G, Alston, KL, Bigner, DD, and Zalutsky, MR. "Nepsilon-(3-[*I]Iodobenzoyl)-Lys5-Nalpha-maleimido-Gly1-GEEEK ([*I]IB-Mal-D-GEEEK): a radioiodinated prosthetic group containing negatively charged D-glutamates for labeling internalizing monoclonal antibodies." Bioconjug Chem 17.4 (July 2006): 1085-1092.
PMID
16848419
Source
pubmed
Published In
Bioconjugate Chemistry
Volume
17
Issue
4
Publish Date
2006
Start Page
1085
End Page
1092
DOI
10.1021/bc0600766

A novel low molecular weight inhibitor of focal adhesion kinase and insulin-like growth factor-1 receptor, TAE226, inhibits glioma growth.

11505 Background: Glioblastomas are highly lethal cancers that resist current therapies. Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase overexpressed in glioblastoma patient specimens that may promote glioma growth and invasion by increasing cellular adhesion, migration, invasion, proliferation. TAE226 is a novel low molecular weight inhibitor of several kinases that demonstrates in vitro activity primarily against FAK with activity against insulin-like growth factor-1 receptor (IGF1R) at higher concentrations. METHODS: As FAK and IGF1R are potential molecular targets in glioblastomas, we examined the efficacy of TAE226 against human glioma cell lines and xenografts. RESULTS: TAE226 inhibited the activating phosphorylation of FAK at submicromolar concentrations with residue specific preference. Downstream effectors (Akt and ERK) were inhibited at slightly higher concentrations. TAE226 demonstrated a concentration-dependent decrease in cellular proliferation with an associated G2 cell cycle arrest in multiple glioma cell lines, whereas TAE226 potently induced apoptosis in a concentration-dependent manner in only one of four cell lines tested. TAE226 also induced a concentration-dependent decrease in cellular adhesion, migration, and invasion. In preliminary animal studies, a limited course of orally administered TAE226 (100 mg/kg qd 5 days on/2 days off/5 days) was well tolerated with minimal weight loss. TAE226 induced a modest growth delay of human glioma xenografts grown in a subcutaneous location in athymic mice (3 to 4 days delay, p < 0.001). In addition, mice bearing orthotopic intracranial human glioma xenografts demonstrated a modest increase in median survival (3.5 days, p = 0.078). Despite the modest degree of the tumor responses, these results are superior to other low molecular weight inhibitors, such as epidermal growth factor receptor (EGFR) inhibitors. As glioma xenografts often grow without invasion, these results may underestimate the efficacy of targeting FAK as FAK plays a major role in tumor invasion. CONCLUSION: TAE226 demonstrates modest activity as monotherapy against malignant gliomas and warrants further investigation, potentially in combination with other therapies. [Table: see text].

Authors
Rich, JN; Shi, Q; Hjelmeland, AB; Keir, ST; Wickman, S; Wu, G; Jackson, D; Ohmori, O; Bigner, DD; Friedman, HS
MLA Citation
Rich, JN, Shi, Q, Hjelmeland, AB, Keir, ST, Wickman, S, Wu, G, Jackson, D, Ohmori, O, Bigner, DD, and Friedman, HS. "A novel low molecular weight inhibitor of focal adhesion kinase and insulin-like growth factor-1 receptor, TAE226, inhibits glioma growth." J Clin Oncol 24.18_suppl (June 20, 2006): 11505-.
PMID
27954359
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
11505

Tumor-specific peptide vaccination in newly-diagnosed patients with GBM.

2529 Background: Despite multimodality approaches, survival with GBM is dismal. Induction of immune responses to suppress the infiltrative, residual component with an easily manufactured and administered immunotherapy has been a theoretical ideal. The epidermal growth factor receptor variant III (EGFRvIII) is a tumor-specific cell surface protein expressed on approximately 40% of GBMs. METHODS: Newly-diagnosed GBM patients with a gross-total resection, a KPS ≥70, and EGFRvIII+, after undergoing radiation with concurrent temozolomide without tumor progression, were eligible to receive EGFRvIII peptide vaccination i.d. with GM-CSF. Primary endpoint was safety. RESULTS: Accrual began in 06/14/2004 and is now complete. 19 patients were enrolled. Median follow-up is 18 months. Toxicity was minimal and without evidence of autoimmunity. Humoral and cellular immune responses were generated. Median TTP from surgery in vaccine-treated patients is 12 months (n = 12), comparing favorably with a historical matched unvaccinated cohort (gross total resection without progression during radiation, KPS≥70, EGFRvIII+) that had a median TTP of 7.1 months (n = 39) (p = 0.0058). These results also compared favorably with those reported for concurrent temozolomide and radiation followed by adjuvant temozolomide, with a median TTP of 6.9 months. Median survival in this trial has exceeded 18 months which compares favorably to all published analyses accounting for all known prognostic indicators. Among recurrent tumors evaluated by immunohistochemistry, 100% no longer expressed the EGFRvIII, suggesting immunological activation that eliminated EGFRvIII-expressing cells, as well as one potential mechanism of treatment failure. CONCLUSIONS: EGFRvIII peptide vaccination warrants further investigation in a larger randomized clinical trial in patients with EGFRvIII-expressing tumors. No significant financial relationships to disclose.

Authors
Heimberger, AB; Hussain, SF; Aldape, K; Sawaya, R; Archer, GA; Friedman, H; Reardon, D; Friedman, A; Bigner, D; Sampson, JH
MLA Citation
Heimberger, AB, Hussain, SF, Aldape, K, Sawaya, R, Archer, GA, Friedman, H, Reardon, D, Friedman, A, Bigner, D, and Sampson, JH. "Tumor-specific peptide vaccination in newly-diagnosed patients with GBM." J Clin Oncol 24.18_suppl (June 20, 2006): 2529-.
PMID
27955024
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
18_suppl
Publish Date
2006
Start Page
2529

Tumor-specific peptide vaccination in newly-diagnosed patients with GBM.

Authors
Heimberger, AB; Hussain, SF; Aldape, K; Sawaya, R; Archer, GA; Friedman, H; Reardon, D; Friedman, A; Bigner, D; Sampson, JH
MLA Citation
Heimberger, AB, Hussain, SF, Aldape, K, Sawaya, R, Archer, GA, Friedman, H, Reardon, D, Friedman, A, Bigner, D, and Sampson, JH. "Tumor-specific peptide vaccination in newly-diagnosed patients with GBM." June 20, 2006.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
24
Issue
18
Publish Date
2006
Start Page
107S
End Page
107S

Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results.

UNLABELLED: Results from animal experiments have shown that human IgG2/mouse chimeric antitenascin 81C6 (ch81C6) monoclonal antibody exhibited higher tumor accumulation and enhanced stability compared with its murine parent. Our objective was to determine the effect of these differences on the maximum tolerated dose (MTD), pharmacokinetics, dosimetry, and antitumor activity of (131)I-ch81C6 administered into the surgically created resection cavity (SCRC) of malignant glioma patients. METHODS: In this phase I trial, eligible patients received a single injection of (131)I-ch81C6 administered through a Rickham catheter into the SCRC. Patients were stratified as newly diagnosed and untreated (stratum A), newly diagnosed after external beam radiotherapy (XRT) (stratum B), and recurrent (stratum C). (131)I-ch81C6 was administered either before (stratum A) or after (stratum B) conventional XRT for newly diagnosed patients. In addition, chemotherapy was prescribed for all patients after (131)I-ch81C6 administration. Dose escalation was performed independently for each stratum. Patients were observed for toxicity and response until death or progressive disease. RESULTS: We treated 47 patients with (131)I-ch81C6 doses up to 4.44 GBq (120 mCi), including 35 with newly diagnosed tumors (strata A and B) and 12 with recurrent disease (stratum C). Dose-limiting hematologic toxicity defined the MTD to be 2.96 GBq (80 mCi) for all patients, regardless of treatment strata. Neurologic dose-limiting toxicity developed in 3 patients; however, none required further surgery to debulk radiation necrosis. Median survival was 88.6 wk and 65.0 wk for newly diagnosed and recurrent patients, respectively. CONCLUSION: The MTD of (131)I-ch81C6 is 2.96 GBq (80 mCi) because of dose-limiting hematologic toxicity. Although encouraging survival was observed, (131)I-ch81C6 was associated with greater hematologic toxicity, probably due to the enhanced stability of the IgG2 construct, than previously observed with (131)I-murine 81C6.

Authors
Reardon, DA; Quinn, JA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Pegram, CN; Provenzale, JM; Dowell, JM; Rich, JN; Vredenburgh, JJ; Desjardins, A; Sampson, JH; Gururangan, S; Wong, TZ; Badruddoja, MA; Zhao, X-G; Bigner, DD; Zalutsky, MR
MLA Citation
Reardon, DA, Quinn, JA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Pegram, CN, Provenzale, JM, Dowell, JM, Rich, JN, Vredenburgh, JJ, Desjardins, A, Sampson, JH, Gururangan, S, Wong, TZ, Badruddoja, MA, Zhao, X-G, Bigner, DD, and Zalutsky, MR. "Novel human IgG2b/murine chimeric antitenascin monoclonal antibody construct radiolabeled with 131I and administered into the surgically created resection cavity of patients with malignant glioma: phase I trial results." J Nucl Med 47.6 (June 2006): 912-918.
PMID
16741299
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
47
Issue
6
Publish Date
2006
Start Page
912
End Page
918

Patterns of exercise across the cancer trajectory in brain tumor patients.

BACKGROUND: Exercise may represent a supportive intervention that may complement existing neurooncologic therapies and address a multitude of therapy-induced debilitating side effects in patients with brain tumors. Given the limited evidence, the authors conducted a survey to examine the exercise patterns of brain tumor patients across the cancer trajectory. METHODS: Using a cross-sectional design, 386 brain tumor patients who received treatment at the Brain Tumor Center at Duke University were sent a questionnaire that assessed self-reported exercise behavior prior to diagnosis, during adjuvant therapy, and after the completion of therapy. RESULTS: The response rate was 28% (106 of 383 patients). Descriptive analyses indicated that 42%, 38%, and 41% of participants, respectively, met national exercise prescription guidelines prior to diagnosis, during treatment, and after the completion of adjuvant therapy. Repeated measures analyses indicated no significant changes in the majority of exercise behavior outcomes over the cancer trajectory. However, exploratory analyses indicated that males and younger participants may be at the greatest risk of reducing exercise levels after a brain tumor diagnosis. These analyses remained unchanged after controlling for relevant demographic and medical covariates. CONCLUSIONS: A relatively high percentage of brain tumor patients are exercising at recommended levels across the cancer trajectory. Moreover, these patients have unique exercise patterns that may be modified by select demographic variables. This preliminary study provides important informative data for future studies examining the potential role of exercise in patients diagnosed with neurologic malignancies.

Authors
Jones, LW; Guill, B; Keir, ST; Carter B S, K; Friedman, HS; Bigner, DD; Reardon, DA
MLA Citation
Jones, LW, Guill, B, Keir, ST, Carter B S, K, Friedman, HS, Bigner, DD, and Reardon, DA. "Patterns of exercise across the cancer trajectory in brain tumor patients." Cancer 106.10 (May 15, 2006): 2224-2232.
PMID
16586497
Source
pubmed
Published In
Cancer
Volume
106
Issue
10
Publish Date
2006
Start Page
2224
End Page
2232
DOI
10.1002/cncr.21858

Therapeutic aspects of chaperones/heat-shock proteins in neuro-oncology.

Tumors of the CNS frequently have devastating consequences in terms of cognitive and motor function, personality and mortality. Despite decades of work, current therapies have done little to alter the course of these deadly diseases. The discovery that chaperones/heat-shock proteins play an important role in tumor biology and immunology have sparked much interest in utilizing these proteins as targets of therapeutics, or as therapeutics themselves, in the treatments of a variety of cancers. Neuro-oncology has only recently taken notice of these entities, and the purpose of this review is to provide a background, an update and a view to the future for the roles of chaperones/heat-shock proteins in the treatment of brain tumors.

Authors
Graner, MW; Bigner, DD
MLA Citation
Graner, MW, and Bigner, DD. "Therapeutic aspects of chaperones/heat-shock proteins in neuro-oncology." Expert Rev Anticancer Ther 6.5 (May 2006): 679-695. (Review)
PMID
16759160
Source
pubmed
Published In
Expert Review of Anticancer Therapy
Volume
6
Issue
5
Publish Date
2006
Start Page
679
End Page
695
DOI
10.1586/14737140.6.5.679

Comparison of intratumoral bolus injection and convection-enhanced delivery of radiolabeled antitenascin monoclonal antibodies.

OBJECTIVES: Convection-enhanced delivery (CED) is a novel technique used to deliver agents to the brain parenchyma for treatment of neoplastic, infectious, and degenerative conditions. The purpose of this study was to determine if CED would provide a larger volume of distribution (Vd) of a radiolabeled monoclonal antibody (mAb) than a bolus injection. METHODS: Patients harboring a recurrent glioblastoma multiforme that reacted with the antitenascin mAb 81C6 during immunohistochemical analysis were randomized to receive an intratumoral injection of the human-murine chimeric mAb Ch81C6, which had been labeled with the 123I tracer. The mAb was administered by either a bolus injection or CED via a stereotactically placed catheter; between 48 and 72 hours later the mAb was again administered using the other technique. Injections of escalating doses of a 131I-labeled therapeutic mAb were then delivered using the technique shown to produce the largest Vd by single-photon emission computerized tomography. CONCLUSIONS: Convection-enhanced delivery has enormous potential for administering drugs to sites within the central nervous system. For the relatively small volumes injected in this study, however, CED did not provide a significant increase in the Vd when compared with the bolus injection. Nevertheless, a clear cross-over effect was seen, which was probably related to the temporal proximity of the two infusions.

Authors
Sampson, JH; Akabani, G; Friedman, AH; Bigner, D; Kunwar, S; Berger, MS; Bankiewicz, KS
MLA Citation
Sampson, JH, Akabani, G, Friedman, AH, Bigner, D, Kunwar, S, Berger, MS, and Bankiewicz, KS. "Comparison of intratumoral bolus injection and convection-enhanced delivery of radiolabeled antitenascin monoclonal antibodies. (Published online)" Neurosurg Focus 20.4 (April 15, 2006): E14-.
PMID
16709019
Source
pubmed
Published In
Neurosurgical focus
Volume
20
Issue
4
Publish Date
2006
Start Page
E14
DOI
10.3171/foc.2006.20.4.9

Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme.

PURPOSE: More brain tumor markers are required for prognosis and targeted therapy. We have identified and validated promising molecular therapeutic glioblastoma multiforme (GBM) targets: human transmembrane glycoprotein nonmetastatic melanoma protein B (GPNMB(wt)) and a splice variant form (GPNMB(sv), a 12-amino-acid in-frame insertion in the extracellular domain). EXPERIMENTAL DESIGN: We have done genetic and immunohistochemical evaluation of human GBM to determine incidence, distribution, and pattern of localization of GPNMB antigens in brain tumors as well as survival analyses. RESULTS: Quantitative real-time PCR on 50 newly diagnosed GBM patient tumor samples indicated that 35 of 50 GBMs (70%) were positive for GPNMB(wt+sv) transcripts and 15 of 50 GBMs (30%) were positive for GPNMB(sv) transcripts. Normal brain samples expressed little or no GPNMB mRNA. We have isolated and characterized an anti-GPNMB polyclonal rabbit antiserum (2640) and two IgG2b monoclonal antibodies (mAb; G11 and U2). The binding affinity constants of the mAbs ranged from 0.27 x 10(8) to 9.6 x 10(8) M(-1) measured by surface plasmon resonance with immobilized GPNMB, or 1.7 to 2.1 x 10(8) M(-1) by Scatchard analyses with cell-expressed GPNMB. Immunohistochemical analysis detected GPNMB in a membranous and cytoplasmic pattern in 52 of 79 GBMs (66%), with focal perivascular reactivity in approximately 27%. Quantitative flow cytometric analysis revealed GPNMB cell surface molecular density of 1.1 x 10(4) to 7.8 x 10(4) molecules per cell, levels sufficient for mAb targeting. Increased GPNMB mRNA levels correlated with elevated GPNMB protein expression in GBM biopsy samples. Univariate and multivariate analyses correlated expression of GPNMB with survival of 39 GBM patients using RNA expression and immunohistochemical data, establishing that patients with relatively high mRNA GPNMB transcript levels (wt+sv and wt), >3-fold over normal brain, as well as positive immunohistochemistry, have a significantly higher risk of death (hazard ratios, 3.0, 2.2, and 2.8, respectively). CONCLUSIONS: Increased mRNA and protein levels in GBM patient biopsy samples correlated with higher survival risk; as a detectable surface membrane protein in glioma cells, the data indicate that GPNMB is a potentially useful tumor-associated antigen and prognostic predictor for therapeutic approaches with malignant gliomas or any malignant tumor that expresses GPNMB.

Authors
Kuan, C-T; Wakiya, K; Dowell, JM; Herndon, JE; Reardon, DA; Graner, MW; Riggins, GJ; Wikstrand, CJ; Bigner, DD
MLA Citation
Kuan, C-T, Wakiya, K, Dowell, JM, Herndon, JE, Reardon, DA, Graner, MW, Riggins, GJ, Wikstrand, CJ, and Bigner, DD. "Glycoprotein nonmetastatic melanoma protein B, a potential molecular therapeutic target in patients with glioblastoma multiforme." Clin Cancer Res 12.7 Pt 1 (April 1, 2006): 1970-1982.
PMID
16609006
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
7 Pt 1
Publish Date
2006
Start Page
1970
End Page
1982
DOI
10.1158/1078-0432.CCR-05-2797

Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma.

Immunosuppression is frequently associated with malignancy and is particularly severe in patients with malignant glioma. Anergy and counterproductive shifts toward T(H)2 cytokine production are long-recognized T-cell defects in these patients whose etiology has remained elusive for >30 years. We show here that absolute counts of both CD4(+) T cells and CD4(+)CD25(+)FOXP3(+)CD45RO(+) T cells (T(regs)) are greatly diminished in patients with malignant glioma, but T(regs) frequently represent an increased fraction of the remaining CD4 compartment. This increased T(reg) fraction, despite reduced counts, correlates with and is sufficient to elicit the characteristic manifestations of impaired patient T-cell responsiveness in vitro. Furthermore, T(reg) removal eradicates T-cell proliferative defects and reverses T(H)2 cytokine shifts, allowing T cells from patients with malignant glioma to function in vitro at levels equivalent to those of normal, healthy controls. Such restored immune function may give license to physiologic antiglioma activity, as in vivo, T(reg) depletion proves permissive for spontaneous tumor rejection in a murine model of established intracranial glioma. These findings dramatically alter our understanding of depressed cellular immune function in patients with malignant glioma and advance a role for T(regs) in facilitating tumor immune evasion in the central nervous system.

Authors
Fecci, PE; Mitchell, DA; Whitesides, JF; Xie, W; Friedman, AH; Archer, GE; Herndon, JE; Bigner, DD; Dranoff, G; Sampson, JH
MLA Citation
Fecci, PE, Mitchell, DA, Whitesides, JF, Xie, W, Friedman, AH, Archer, GE, Herndon, JE, Bigner, DD, Dranoff, G, and Sampson, JH. "Increased regulatory T-cell fraction amidst a diminished CD4 compartment explains cellular immune defects in patients with malignant glioma." Cancer Res 66.6 (March 15, 2006): 3294-3302.
PMID
16540683
Source
pubmed
Published In
Cancer Research
Volume
66
Issue
6
Publish Date
2006
Start Page
3294
End Page
3302
DOI
10.1158/0008-5472.CAN-05-3773

Recent advances in the treatment of malignant astrocytoma.

Malignant gliomas, including the most common subtype, glioblastoma multiforme (GBM), are among the most devastating of neoplasms. Their aggressive infiltration in the CNS typically produces progressive and profound disability--ultimately leading to death in nearly all cases. Improvement in outcome has been elusive despite decades of intensive clinical and laboratory research. Surgery and radiotherapy, the traditional cornerstones of therapy, provide palliative benefit, while the value of chemotherapy has been marginal and controversial. Limited delivery and tumor heterogeneity are two fundamental factors that have critically hindered therapeutic progress. A novel chemoradiotherapy approach, consisting of temozolomide administered concurrently during radiotherapy followed by adjuvant systemic temozolomide, has recently demonstrated a meaningful, albeit modest, improvement in overall survival for newly diagnosed GBM patients. As cell-signaling alterations linked to the development and progression of gliomas are being increasingly elucidated, targeted therapies have rapidly entered preclinical and clinical evaluation. Responses to therapies that function via DNA damage have been associated with specific mediators of resistance that may also be subject to targeted therapies. Other approaches include novel locoregional delivery techniques to overcome barriers of delivery. The simultaneous development of multiple advanced therapies based on specific tumor biology may finally offer glioma patients improved survival.

Authors
Reardon, DA; Rich, JN; Friedman, HS; Bigner, DD
MLA Citation
Reardon, DA, Rich, JN, Friedman, HS, and Bigner, DD. "Recent advances in the treatment of malignant astrocytoma." J Clin Oncol 24.8 (March 10, 2006): 1253-1265. (Review)
PMID
16525180
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
8
Publish Date
2006
Start Page
1253
End Page
1265
DOI
10.1200/JCO.2005.04.5302

Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma.

PURPOSE: To determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of gefitinib, a receptor tyrosine kinase inhibitor of the epidermal growth factor receptor, plus sirolimus, an inhibitor of the mammalian target of rapamycin, among patients with recurrent malignant glioma. PATIENTS AND METHODS: Gefitinib and sirolimus were administered on a continuous daily dosing schedule at dose levels that were escalated in successive cohorts of malignant glioma patients at any recurrence who were stratified based on concurrent use of CYP3A-inducing anticonvulsants [enzyme-inducing antiepileptic drugs, (EIAED)]. Pharmacokinetic and archival tumor biomarker data were also assessed. RESULTS: Thirty-four patients with progressive disease after prior radiation therapy and chemotherapy were enrolled, including 29 (85%) with glioblastoma multiforme and 5 (15%) with anaplastic glioma. The MTD was 500 mg of gefitinib plus 5 mg of sirolimus for patients not on EIAEDs and 1,000 mg of gefitinib plus 10 mg of sirolimus for patients on EIAEDs. DLTs included mucositis, diarrhea, rash, thrombocytopenia, and hypertriglyceridemia. Gefitinib exposure was not affected by sirolimus administration but was significantly lowered by concurrent EIAED use. Two patients (6%) achieved a partial radiographic response, and 13 patients (38%) achieved stable disease. CONCLUSION: We show that gefitinib plus sirolimus can be safely coadministered on a continuous, daily dosing schedule, and established the recommended dose level of these agents in combination for future phase 2 clinical trials.

Authors
Reardon, DA; Quinn, JA; Vredenburgh, JJ; Gururangan, S; Friedman, AH; Desjardins, A; Sathornsumetee, S; Herndon, JE; Dowell, JM; McLendon, RE; Provenzale, JM; Sampson, JH; Smith, RP; Swaisland, AJ; Ochs, JS; Lyons, P; Tourt-Uhlig, S; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Reardon, DA, Quinn, JA, Vredenburgh, JJ, Gururangan, S, Friedman, AH, Desjardins, A, Sathornsumetee, S, Herndon, JE, Dowell, JM, McLendon, RE, Provenzale, JM, Sampson, JH, Smith, RP, Swaisland, AJ, Ochs, JS, Lyons, P, Tourt-Uhlig, S, Bigner, DD, Friedman, HS, and Rich, JN. "Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma." Clin Cancer Res 12.3 Pt 1 (February 1, 2006): 860-868.
PMID
16467100
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
12
Issue
3 Pt 1
Publish Date
2006
Start Page
860
End Page
868
DOI
10.1158/1078-0432.CCR-05-2215

Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results.

PURPOSE: To assess the efficacy and toxicity of intraresection cavity iodine-131-labeled murine antitenascin monoclonal antibody 81C6 (131I-m81C6) among recurrent malignant brain tumor patients. PATIENTS AND METHODS: In this phase II trial, 100 mCi of 131I-m81C6 was injected directly into the surgically created resection cavity (SCRC) of 43 patients with recurrent malignant glioma (glioblastoma multiforme [GBM], n = 33; anaplastic astrocytoma [AA], n = 6; anaplastic oligodendroglioma [AO], n = 2; gliosarcoma [GS], n = 1; and metastatic adenocarcinoma, n = 1) followed by chemotherapy. RESULTS: With a median follow-up of 172 weeks, 63% and 59% of patients with GBM/GS and AA/AO tumors were alive at 1 year. Median overall survival for patients with GBM/GS and AA/AO tumors was 64 and 99 weeks, respectively. Ten patients (23%) developed acute hematologic toxicity. Five patients (12%) developed acute reversible neurotoxicity. One patient (2%) developed irreversible neurotoxicity. No patients required reoperation for radionecrosis. CONCLUSION: In this single-institution phase II study, administration of 100 mCi of 131I-m81C6 to recurrent malignant glioma patients followed by chemotherapy is associated with a median survival that is greater than that of historical controls treated with surgery plus iodine-125 brachytherapy. Furthermore, toxicity was acceptable. Administration of a fixed millicurie dose resulted in a wide range of absorbed radiation doses to the SCRC. We are now conducting a phase II trial, approved by the US Food and Drug Administration, using patient-specific 131I-m81C6 dosing, to deliver 44 Gy to the SCRC followed by standardized chemotherapy. A phase III multicenter trial with patient-specific dosing is planned.

Authors
Reardon, DA; Akabani, G; Coleman, RE; Friedman, AH; Friedman, HS; Herndon, JE; McLendon, RE; Pegram, CN; Provenzale, JM; Quinn, JA; Rich, JN; Vredenburgh, JJ; Desjardins, A; Gururangan, S; Badruddoja, M; Dowell, JM; Wong, TZ; Zhao, X-G; Zalutsky, MR; Bigner, DD
MLA Citation
Reardon, DA, Akabani, G, Coleman, RE, Friedman, AH, Friedman, HS, Herndon, JE, McLendon, RE, Pegram, CN, Provenzale, JM, Quinn, JA, Rich, JN, Vredenburgh, JJ, Desjardins, A, Gururangan, S, Badruddoja, M, Dowell, JM, Wong, TZ, Zhao, X-G, Zalutsky, MR, and Bigner, DD. "Salvage radioimmunotherapy with murine iodine-131-labeled antitenascin monoclonal antibody 81C6 for patients with recurrent primary and metastatic malignant brain tumors: phase II study results." J Clin Oncol 24.1 (January 1, 2006): 115-122.
PMID
16382120
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
24
Issue
1
Publish Date
2006
Start Page
115
End Page
122
DOI
10.1200/JCO.2005.03.4082

Antiepidermal growth factor variant III scFv fragment: effect of radioiodination method on tumor targeting and normal tissue clearance.

INTRODUCTION: MR1-1 is a single-chain Fv (scFv) fragment that binds with high affinity to epidermal growth factor receptor variant III, which is overexpressed on gliomas and other tumors but is not present on normal tissues. The objective of this study was to evaluate four different methods for labeling MR1-1 scFv that had been previously investigated for the radioiodinating of an intact anti-epidermal growth factor receptor variant III (anti-EGFRvIII) monoclonal antibody (mAb) L8A4. METHODS: The MR1-1 scFv was labeled with (125)I/(131)I using the Iodogen method, and was also radiohalogenated with acylation agents bearing substituents that were positively charged--N-succinimidyl-3-[*I]iodo-5-pyridine carboxylate and N-succinimidyl-4-guanidinomethyl-3-[*I]iodobenzoate ([*I]SGMIB)--and negatively charged--N-succinimidyl-3-[*I]iodo-4-phosphonomethylbenzoate ([*I]SIPMB). In vitro internalization assays were performed with the U87MGDeltaEGFR cell line, and the tissue distribution of the radioiodinated scFv fragments was evaluated in athymic mice bearing subcutaneous U87MGDeltaEGFR xenografts. RESULTS AND CONCLUSION: As seen previously with the anti-EGFRvIII IgG mAb, retention of radioiodine activity in U87MGDeltaEGFR cells in the internalization assay was labeling method dependent, with SGMIB and SIPMB yielding the most prolonged retention. However, unlike the case with the intact mAb, the results of the internalization assays were not predictive of in vivo tumor localization capacity of the labeled scFv. Renal activity was dependent on the nature of the labeling method. With MR1-1 labeled using SIPMB, kidney uptake was highest and most prolonged; catabolism studies indicated that this uptake primarily was in the form of epsilon-N-3-[*I]iodo-4-phosphonomethylbenzoyl lysine.

Authors
Shankar, S; Vaidyanathan, G; Kuan, C-T; Bigner, DD; Zalutsky, MR
MLA Citation
Shankar, S, Vaidyanathan, G, Kuan, C-T, Bigner, DD, and Zalutsky, MR. "Antiepidermal growth factor variant III scFv fragment: effect of radioiodination method on tumor targeting and normal tissue clearance." Nucl Med Biol 33.1 (January 2006): 101-110.
PMID
16459265
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
33
Issue
1
Publish Date
2006
Start Page
101
End Page
110
DOI
10.1016/j.nucmedbio.2005.08.004

Neuro-Oncology: Editorial

Authors
Bigner, DD; Yung, WKA; James, CD; Cohn, SA
MLA Citation
Bigner, DD, Yung, WKA, James, CD, and Cohn, SA. "Neuro-Oncology: Editorial." Neuro-Oncology 8.4 (2006): 289--.
Source
scival
Published In
Neuro-Oncology
Volume
8
Issue
4
Publish Date
2006
Start Page
289-
DOI
10.1215/15228517-2006-018

Work exposures to animal neurocarcinogens

The initiation of brain tumors has been demonstrated in animals exposed to industrial chemicals, results which have not been demonstrated in humans. This report describes the National Occupation Exposure Survey conducted by the National Institute of Occupational Safety and Health during the years 1981-1983, which included information about 16 known and suspected animal neurocarcinogens. Acrylonitrile, ethylene oxide, and 1-H-benzotriazole had national exposure estimates of more than 50,000 workers. The health services industry had the largest number of workers potentially exposed to a single agent and the most diverse exposures in the workplace. These data provide some evidence for the pattern and presence of animal neurocarcinogens in the occupational environment and provide a basis on which to begin to develop occupational exposure tools and to prioritize further research.

Authors
Davis, FG; Erdal, S; Williams, L; Bigner, D
MLA Citation
Davis, FG, Erdal, S, Williams, L, and Bigner, D. "Work exposures to animal neurocarcinogens." International Journal of Occupational and Environmental Health 12.1 (2006): 16-23.
PMID
16523978
Source
scival
Published In
International Journal of Occupational and Environmental Health
Volume
12
Issue
1
Publish Date
2006
Start Page
16
End Page
23

Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity.

In normal epithelial tissues, the multifunctional cytokine transforming growth factor-beta (TGF-beta) acts as a tumor suppressor through growth inhibition and induction of differentiation whereas in advanced cancers, TGF-beta promotes tumor progression through induction of tumor invasion, neoangiogenesis, and immunosuppression. The molecular mechanisms through which TGF-beta shifts from a tumor suppressor to a tumor enhancer are poorly understood. We now show a role for the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in repressing the protumorigenic effects of TGF-beta. The TGF-beta effector SMAD3 inducibly interacts with PTEN on TGF-beta treatment under endogenous conditions. RNA interference (RNAi) suppression of PTEN expression enhances SMAD3 transcriptional activity and TGF-beta-mediated induction of SMAD3 target genes whereas reconstitution of PTEN in a null cancer cell line represses the expression of TGF-beta-regulated target genes. Targeting PTEN expression through RNAi in a PTEN wild-type cell line increases TGF-beta-mediated invasion but does not affect TGF-beta-mediated growth inhibition. Reconstitution of PTEN expression in a PTEN-null cell line blocks TGF-beta-induced invasion but does not modulate TGF-beta-mediated growth regulation. These effects are distinct from Akt and Forkhead family members that also interact with SMAD3 to regulate apoptosis or proliferation, respectively. Pharmacologic inhibitors targeting TGF-beta receptors and phosphatidylinositol 3-kinase signaling downstream from PTEN cooperate to block TGF-beta-mediated invasion. Thus, the loss of PTEN expression in human cancers may contribute to a role for TGF-beta as a tumor enhancer with specific effects on cellular motility and invasion.

Authors
Hjelmeland, AB; Hjelmeland, MD; Shi, Q; Hart, JL; Bigner, DD; Wang, X-F; Kontos, CD; Rich, JN
MLA Citation
Hjelmeland, AB, Hjelmeland, MD, Shi, Q, Hart, JL, Bigner, DD, Wang, X-F, Kontos, CD, and Rich, JN. "Loss of phosphatase and tensin homologue increases transforming growth factor beta-mediated invasion with enhanced SMAD3 transcriptional activity." Cancer Res 65.24 (December 15, 2005): 11276-11281.
PMID
16357132
Source
pubmed
Published In
Cancer Research
Volume
65
Issue
24
Publish Date
2005
Start Page
11276
End Page
11281
DOI
10.1158/0008-5472.CAN-05-3016

Signal transduction through substance P receptor in human glioblastoma cells: roles for Src and PKCdelta.

Substance P receptor (SPR), a G protein-coupled receptor (GPCR), is found in human glioblastomas, and has been implicated in their growth. Consistent with a role for SPR in cell growth, activation of SPR in U373 MG human glioblastoma cells leads to the phosphorylation of mitogen-activated protein kinases [extracellular signal-regulated kinase 1 and 2 (ERK1/2)] and stimulation of cell proliferation. The purpose of the present study was to elucidate the pathway through which these actions occur. Using either the epidermal growth factor receptor (EGFR) kinase inhibitor, AG 1478, or a small-interfering RNA (siRNA) directed against human EGFR, we found that transactivation of EGFR by SPR is only marginally involved in SP-dependent ERK1/2 phosphorylation. Src, however, is shown to be a major component of SPR signaling because the Src kinase inhibitor, PP2, and a kinase-dead Src mutant both inhibit SP-dependent ERK1/2 phosphorylation. We also report that SPR stimulates the phosphorylation of protein kinase Cdelta(PKCdelta), and that this stimulation is blocked by PP2. SP-dependent ERK1/2 phosphorylation is also blocked by rottlerin, a PKCdelta inhibitor, and the calcium scavenger, BAPTA/AM. Finally, rottlerin and PP2 were both found to inhibit the growth of several glioblastoma cell lines, underscoring the potential of these agents to block glioblastoma growth.

Authors
Yamaguchi, K; Richardson, MD; Bigner, DD; Kwatra, MM
MLA Citation
Yamaguchi, K, Richardson, MD, Bigner, DD, and Kwatra, MM. "Signal transduction through substance P receptor in human glioblastoma cells: roles for Src and PKCdelta." Cancer Chemother Pharmacol 56.6 (December 2005): 585-593.
PMID
16012865
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
56
Issue
6
Publish Date
2005
Start Page
585
End Page
593
DOI
10.1007/s00280-005-1030-3

ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors.

PURPOSE: Primary central nervous system (CNS) tumors represent a diverse group of tumor types with heterogeneous molecular mechanisms that underlie their formation and maintenance. CNS tumors depend on angiogenesis and often display increased activity of ErbB-associated pathways. Current nonspecific therapies frequently have poor efficacy in many of these tumor types, so there is a pressing need for the development of novel targeted therapies. EXPERIMENTAL DESIGN: ZD6474 is a novel, orally available low molecular weight inhibitor of the kinase activities associated with vascular endothelial growth factor receptor-2 and epidermal growth factor receptor. We hypothesized that ZD6474 may provide benefit in the treatment of several CNS tumor types. RESULTS: In mice bearing established s.c. tumor xenografts of CNS tumors (malignant glioma and ependymoma) or rhabdomyosarcoma, a limited course of ZD6474 treatment produced significant tumor growth delays and a high rate of partial tumor regression in most models examined. Mice with i.c. malignant glioma xenografts treated with ZD6474 experienced a significant prolongation of survival. Tumors from mice treated with ZD6474 displayed a lower proliferative index and disrupted tumor vascularity. Notably, some of these models are insensitive to low molecular weight kinase inhibitors targeting only vascular endothelial growth factor receptor-2 or epidermal growth factor receptor functions, suggesting that the combined disruption of both epidermal growth factor receptor and vascular endothelial growth factor receptor-2 activities may significantly increase tumor control. CONCLUSIONS: In conclusion, ZD6474 shows significant activity against xenograft models of several primary human CNS tumor types. Consideration for clinical development in this disease setting seems warranted.

Authors
Rich, JN; Sathornsumetee, S; Keir, ST; Kieran, MW; Laforme, A; Kaipainen, A; McLendon, RE; Graner, MW; Rasheed, BKA; Wang, L; Reardon, DA; Ryan, AJ; Wheeler, C; Dimery, I; Bigner, DD; Friedman, HS
MLA Citation
Rich, JN, Sathornsumetee, S, Keir, ST, Kieran, MW, Laforme, A, Kaipainen, A, McLendon, RE, Graner, MW, Rasheed, BKA, Wang, L, Reardon, DA, Ryan, AJ, Wheeler, C, Dimery, I, Bigner, DD, and Friedman, HS. "ZD6474, a novel tyrosine kinase inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor, inhibits tumor growth of multiple nervous system tumors." Clin Cancer Res 11.22 (November 15, 2005): 8145-8157.
PMID
16299247
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
11
Issue
22
Publish Date
2005
Start Page
8145
End Page
8157
DOI
10.1158/1078-0432.CCR-05-0319

Glioblastoma multiforme and the epidermal growth factor receptor.

Authors
Friedman, HS; Bigner, DD
MLA Citation
Friedman, HS, and Bigner, DD. "Glioblastoma multiforme and the epidermal growth factor receptor." N Engl J Med 353.19 (November 10, 2005): 1997-1999.
PMID
16282174
Source
pubmed
Published In
The New England journal of medicine
Volume
353
Issue
19
Publish Date
2005
Start Page
1997
End Page
1999
DOI
10.1056/NEJMp058186

Survival analysis of presumptive prognostic markers among oligodendrogliomas.

BACKGROUND: Allelic losses of 1p and 19q arms correlate with the oligodendroglial phenotype as well as with sensitivity to radiotherapy and chemotherapy. Furthermore, the DNA repair gene, methylguanine methyltransferase (MGMT), is diminished in 80% of oligodendroglial tumors and represents a possible mechanism for this therapeutic sensitivity. However, the authors questioned the relevance of genetic testing and measuring MGMT levels in tumors that were diagnostic of oligodendroglioma. METHODS: The authors performed a retrospective analysis of 1p, 19q, 9p21, TP53, and MGMT status in 46 patients with oligodendrogliomas to address any relations that may exist among these markers with regard to progression-free survival (PFS) and total survival. Methodologies included comparative genomic hybridization; loss of heterozygosity (LOH) on 1p, 19q, and 9p21; TP53 mutational analysis; and immunohistochemistry for MGMT. RESULTS: The authors found that survival among patients with light microscopically diagnosed oligodendroglial tumors demonstrating LOH of 1p and 19q trended toward statistical significance (P = 0.102 and P = 0.058, respectively). 9p21 LOH was significant as a predictor of PFS only among anaplastic oligodendrogliomas in this cohort (P = 0.033). TP53 mutation was found to be significantly predictive of a shorter survival (P = 0.027) among all patients and exhibited a strong trend toward a shorter PFS (P = 0.060). Low-level MGMT labeling index (LI) (< 20%) was noted in 86% of all oligodendroglial tumors. MGMT LI was not found to correlate with an improved PFS or total survival in this cohort, recognizing that median survival was not reached after a median follow-up of 104 months. CONCLUSIONS: 9p21 and TP53 mutational status assisted in developing a stricter subclassification of these tumors with prognostic significance. MGMT levels were decreased in a majority of oligodendrogliomas.

Authors
McLendon, RE; Herndon, JE; West, B; Reardon, D; Wiltshire, R; Rasheed, BKA; Quinn, J; Friedman, HS; Friedman, AH; Bigner, DD
MLA Citation
McLendon, RE, Herndon, JE, West, B, Reardon, D, Wiltshire, R, Rasheed, BKA, Quinn, J, Friedman, HS, Friedman, AH, and Bigner, DD. "Survival analysis of presumptive prognostic markers among oligodendrogliomas." Cancer 104.8 (October 15, 2005): 1693-1699.
PMID
16116609
Source
pubmed
Published In
Cancer
Volume
104
Issue
8
Publish Date
2005
Start Page
1693
End Page
1699
DOI
10.1002/cncr.21362

Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG. PATIENTS AND METHODS: For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined. RESULTS: The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression. CONCLUSION: This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.

Authors
Quinn, JA; Desjardins, A; Weingart, J; Brem, H; Dolan, ME; Delaney, SM; Vredenburgh, J; Rich, J; Friedman, AH; Reardon, DA; Sampson, JH; Pegg, AE; Moschel, RC; Birch, R; McLendon, RE; Provenzale, JM; Gururangan, S; Dancey, JE; Maxwell, J; Tourt-Uhlig, S; Herndon, JE; Bigner, DD; Friedman, HS
MLA Citation
Quinn, JA, Desjardins, A, Weingart, J, Brem, H, Dolan, ME, Delaney, SM, Vredenburgh, J, Rich, J, Friedman, AH, Reardon, DA, Sampson, JH, Pegg, AE, Moschel, RC, Birch, R, McLendon, RE, Provenzale, JM, Gururangan, S, Dancey, JE, Maxwell, J, Tourt-Uhlig, S, Herndon, JE, Bigner, DD, and Friedman, HS. "Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma." J Clin Oncol 23.28 (October 1, 2005): 7178-7187.
PMID
16192602
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
23
Issue
28
Publish Date
2005
Start Page
7178
End Page
7187
DOI
10.1200/JCO.2005.06.502

GNOSIS: guidelines for neuro-oncology: standards for investigational studies-reporting of phase 1 and phase 2 clinical trials.

We present guidelines to standardize the reporting of phase 1 and phase 2 neuro-oncology trials. The guidelines are also intended to assist with accurate interpretation of results from these trials, to facilitate the peer-review process, and to expedite the publication of important and accurate manuscripts. Our guidelines are summarized in a checklist format that can be used as a framework from which to construct a phase 1 or 2 clinical trial.

Authors
Chang, SM; Reynolds, SL; Butowski, N; Lamborn, KR; Buckner, JC; Kaplan, RS; Bigner, DD
MLA Citation
Chang, SM, Reynolds, SL, Butowski, N, Lamborn, KR, Buckner, JC, Kaplan, RS, and Bigner, DD. "GNOSIS: guidelines for neuro-oncology: standards for investigational studies-reporting of phase 1 and phase 2 clinical trials." Neuro Oncol 7.4 (October 2005): 425-434.
PMID
16212807
Source
pubmed
Published In
Neuro-Oncology
Volume
7
Issue
4
Publish Date
2005
Start Page
425
End Page
434
DOI
10.1215/S1152851705000554

Tenascin and microvessel stromal changes in patients with non-Hodgkin's lymphoma are isolated to the sites of disease and vary in correlation to disease activity.

This study investigated stromal changes in expression of tenascin and vasculogenesis in lymphoma. Documenting the dynamic nature of the stromal changes in lymphoma in relation to response to therapy is helpful in planning new therapies directed at these targets. Two hundred and sixty one samples from 111 patients with varying types of non-Hodgkin's lymphoma were reviewed and examined using immunohistochemistry techniques. Samples were stained for factor VIII - related antigen for microvessel density (MVD) analysis and anti-tenascin antibody for qualitative assessment of the stromal expression. Multiple samples from the same patient were taken at the same point in time to assess whether stromal changes were limited to sites of disease. Multiple samples were examined over the course of a patient's illness to assess whether the stromal changes were modulated according to disease activity. There was a significant increase in tenascin expression and MVD in the sites of disease compared with uninvolved sites (p = 0.01 and p < 0.0001, respectively). In patients who responded to therapy, there was a decrease in the expression of tenascin (p = 0.0049) and MVD (p < 0.0001), and in those with disease progression there was an increase in the tenascin expression (p = 0.0050) and MVD (p < 0.0001). Our results suggest stromal changes are isolated to the sites of disease within patients, allowing targeted therapies to be developed. Further, stromal changes correlate with disease response over the course of the patient's disease. This new finding may have implications for the timing of anti-stromally directed therapies.

Authors
Rizzieri, DA; Wadleigh, M; Wikstrand, CJ; Mann, KP; Sen, F; Peterson, BL; Niedzwiecki, D; Proia, AD; Bigner, DD
MLA Citation
Rizzieri, DA, Wadleigh, M, Wikstrand, CJ, Mann, KP, Sen, F, Peterson, BL, Niedzwiecki, D, Proia, AD, and Bigner, DD. "Tenascin and microvessel stromal changes in patients with non-Hodgkin's lymphoma are isolated to the sites of disease and vary in correlation to disease activity." Leuk Lymphoma 46.10 (October 2005): 1455-1462.
PMID
16194891
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
46
Issue
10
Publish Date
2005
Start Page
1455
End Page
1462
DOI
10.1080/10428190500158060

Chemotherapy and novel therapeutic approaches in malignant glioma.

Glial neoplasms represent 0.5-1% of all cancers in most Western countries. Malignant gliomas are among the most devastating cancers, leading to death in most cases. They present unique challenges due to their location, aggressive biological behavior and diffuse infiltrative growth. Notwithstanding the development of new surgical and radiation techniques in the last thirty years, a cure for malignant gliomas remains elusive. In this article, we will review the standard and new therapies used for malignant gliomas. As standard therapies, surgery, radiation therapy and systemic chemotherapy, are in a continuous process of evolution. Multiple chemotherapies have been used in malignant gliomas, as single agents, in combination, or with different modes of administration, including high-dose chemotherapy with stem cell rescue and intra-arterial chemotherapy. The last decade has been noticeable for the advent of a better understanding of the biology of malignant gliomas. This has stimulated active research in multiples areas and the advent of new treatment strategies. Techniques to circumvent the resistance mechanisms to chemotherapy have been evaluated, tyrosine kinase inhibitors have shown activity in malignant primary brain tumors and radioimmunotherapy remains an area of active research. In this article, we review the past, present and future treatments of malignant gliomas with a special interest on chemotherapy, resistance mechanisms and tyrosine kinase inhibitors.

Authors
Desjardins, A; Rich, JN; Quinn, JA; Vredenburgh, J; Gururangan, S; Sathornsumetee, S; Reardon, DA; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Desjardins, A, Rich, JN, Quinn, JA, Vredenburgh, J, Gururangan, S, Sathornsumetee, S, Reardon, DA, Friedman, AH, Bigner, DD, and Friedman, HS. "Chemotherapy and novel therapeutic approaches in malignant glioma. (Published online)" Front Biosci 10 (September 1, 2005): 2645-2668. (Review)
PMID
15970525
Source
pubmed
Published In
Frontiers in bioscience : a journal and virtual library
Volume
10
Publish Date
2005
Start Page
2645
End Page
2668

Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft.

Temozolomide is a DNA-methylating agent used in the treatment of malignant gliomas. In this study, we have examined if inhibition of poly(ADP-ribose) polymerase (PARP) could increase the cytotoxicity of temozolomide, particularly in cells deficient in DNA mismatch repair. Athymic mice, transplanted with mismatch repair-proficient [D-245 MG] or deficient [D-245 MG (PR)] xenografts, were treated with a combination of temozolomide and the PARP inhibitor, INO-1001. For the tumors deficient in mismatch repair, the most effective dose of INO-1001 was found to be 150 mg/kg, given i.p. thrice at 4-hour intervals with the first injection in combination with 262.5 mg/kg temozolomide (0.75 LD(10)). This dose of temozolomide by itself induced no partial regressions and a 4-day growth delay. In two separate experiments, the combination therapy increased the growth delay by 21.6 and 9.7 days with partial regressions observed in four of eight and three of nine mice, respectively. The addition of INO-1001 had a more modest, yet statistically significant, increase in tumor growth delay in the mismatch repair-proficient xenografts. In these experiments, mice were treated with a lower amount of temozolomide (88 mg/kg), which resulted in growth delays of 43.1 and 39.2 days. When the temozolomide treatment was in combination with 200 mg/kg INO-1001, there was an increase in growth delay to 48.9 and 45.7 days, respectively. These results suggest that inhibition of PARP may increase the efficacy of temozolomide in the treatment of malignant gliomas, particularly in tumors deficient in DNA mismatch repair.

Authors
Cheng, CL; Johnson, SP; Keir, ST; Quinn, JA; Ali-Osman, F; Szabo, C; Li, H; Salzman, AL; Dolan, ME; Modrich, P; Bigner, DD; Friedman, HS
MLA Citation
Cheng, CL, Johnson, SP, Keir, ST, Quinn, JA, Ali-Osman, F, Szabo, C, Li, H, Salzman, AL, Dolan, ME, Modrich, P, Bigner, DD, and Friedman, HS. "Poly(ADP-ribose) polymerase-1 inhibition reverses temozolomide resistance in a DNA mismatch repair-deficient malignant glioma xenograft." Mol Cancer Ther 4.9 (September 2005): 1364-1368.
PMID
16170028
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
4
Issue
9
Publish Date
2005
Start Page
1364
End Page
1368
DOI
10.1158/1535-7163.MCT-05-0128

Chaperone proteins and brain tumors: potential targets and possible therapeutics.

Chaperone proteins are most notable for the proteo- and cyotoprotective capacities they afford during cellular stress. Under conditions of cellular normalcy, chaperones still play integral roles in the folding of nascent polypeptides into functional entities, in assisting in intracellular/intraorganellar transport, in assembly and maintenance of multi-subunit protein complexes, and in aiding and abetting the degradation of senescent proteins. Tumors frequently have relatively enhanced needs for chaperone number and activity because of the stresses of rapid proliferation, increased metabolism, and overall genetic instability. Thus, it may be possible to take advantage of this reliance that tumor cells have on chaperones by pharmacologic and biologic means. Certain chaperones are abundant in the brain, which implies important roles for them. While it is presumed that the requirements of brain tumors for chaperone proteins are similar to those of any other cell type, tumor or otherwise, very little inquiry has been directed at the possibility of using chaperone proteins as therapeutic targets or even as therapeutic agents against central nervous system malignancies. This review highlights some of the research on the functions of chaperone proteins, on what can be done to modify those functions, and on the physiological responses that tumors and organisms can have to chaperone-targeted or chaperone-based therapies. In particular, this review will also underscore areas of research where brain tumors have been part of the field, although in general those instances are few and far between. This relative dearth of research devoted to chaperone protein targets and therapeutics in brain tumors reveals much untrodden turf to explore for potential treatments of these dreadfully refractive diseases.

Authors
Graner, MW; Bigner, DD
MLA Citation
Graner, MW, and Bigner, DD. "Chaperone proteins and brain tumors: potential targets and possible therapeutics." Neuro Oncol 7.3 (July 2005): 260-278. (Review)
PMID
16053701
Source
pubmed
Published In
Neuro-Oncology
Volume
7
Issue
3
Publish Date
2005
Start Page
260
End Page
278
DOI
10.1215/S1152851704001188

Pre-clinical evaluation of D2C7, a monoclonal antibody reactive for both the wild type and variant III mutant epidermal growth factor receptor, for radioimmunotherapy of malignant gliomas

Authors
Boskovitz, A; Pegram, C; Peixoto, K; Zalutsky, MR; Bigner, DD
MLA Citation
Boskovitz, A, Pegram, C, Peixoto, K, Zalutsky, MR, and Bigner, DD. "Pre-clinical evaluation of D2C7, a monoclonal antibody reactive for both the wild type and variant III mutant epidermal growth factor receptor, for radioimmunotherapy of malignant gliomas." July 2005.
Source
wos-lite
Published In
Neuro-Oncology
Volume
7
Issue
3
Publish Date
2005
Start Page
370
End Page
370

Gene expression profiling links invasion-related genes to poor survival in older glioblastoma patients

Authors
Rich, J; Hans, C; Jones, B; McLendon, R; Rasheed, B; Dobra, A; Dressman, H; Bigner, D; Nevins, J; West, M
MLA Citation
Rich, J, Hans, C, Jones, B, McLendon, R, Rasheed, B, Dobra, A, Dressman, H, Bigner, D, Nevins, J, and West, M. "Gene expression profiling links invasion-related genes to poor survival in older glioblastoma patients." July 2005.
Source
wos-lite
Published In
Neuro-Oncology
Volume
7
Issue
3
Publish Date
2005
Start Page
293
End Page
293

PIK3CA is mutated in oligodendrogliomas, astrocytomas, and medulloblastomas and associated with chromosome 1p, 19q LOH in oligodendrogliomas

Authors
Adamson, DC; Broderick, DK; Di, C; Samuels, YR; McLendon, RE; Fults, DW; Velculescu, VE; Rasheed, A; Bigner, DD; Yan, H
MLA Citation
Adamson, DC, Broderick, DK, Di, C, Samuels, YR, McLendon, RE, Fults, DW, Velculescu, VE, Rasheed, A, Bigner, DD, and Yan, H. "PIK3CA is mutated in oligodendrogliomas, astrocytomas, and medulloblastomas and associated with chromosome 1p, 19q LOH in oligodendrogliomas." July 2005.
Source
wos-lite
Published In
Neuro-Oncology
Volume
7
Issue
3
Publish Date
2005
Start Page
345
End Page
345

A novel mechanism of PKA- and PKC-dependent drug resistance in human gliomas involving phosphorylation and metabolic activation of glutathione S-transferase P1 (GSTP1)

Authors
Ali-Osman, F; Lo, H; Antoun, G; Friedman, A; Friedman, H; Bigner, D
MLA Citation
Ali-Osman, F, Lo, H, Antoun, G, Friedman, A, Friedman, H, and Bigner, D. "A novel mechanism of PKA- and PKC-dependent drug resistance in human gliomas involving phosphorylation and metabolic activation of glutathione S-transferase P1 (GSTP1)." July 2005.
Source
wos-lite
Published In
Neuro-Oncology
Volume
7
Issue
3
Publish Date
2005
Start Page
377
End Page
377

Prevalence and prognostic significance of polymorphisms at the glutathione S-transferase M1, M3, P1, and T1 gene loci in human astrocytomas

Authors
Ali-Osman, F; Herndon, JE; Stephenson, L; Davis, F; McCarthy, B; Reardon, D; Friedman, A; McClendon, R; Friedman, H; Bigner, DD
MLA Citation
Ali-Osman, F, Herndon, JE, Stephenson, L, Davis, F, McCarthy, B, Reardon, D, Friedman, A, McClendon, R, Friedman, H, and Bigner, DD. "Prevalence and prognostic significance of polymorphisms at the glutathione S-transferase M1, M3, P1, and T1 gene loci in human astrocytomas." July 2005.
Source
wos-lite
Published In
Neuro-Oncology
Volume
7
Issue
3
Publish Date
2005
Start Page
304
End Page
304

A phase I trial of gefitinib (ZD1 839) plus rapamycin for patients with recurrent malignant glioma.

Authors
Rich, JN; Reardon, DA; Quinn, JA; Vredenburgh, JJ; Desjardins, A; Sathornsumetee, S; Gururangan, S; Lyons, P; Bigner, DD; Friedman, HS
MLA Citation
Rich, JN, Reardon, DA, Quinn, JA, Vredenburgh, JJ, Desjardins, A, Sathornsumetee, S, Gururangan, S, Lyons, P, Bigner, DD, and Friedman, HS. "A phase I trial of gefitinib (ZD1 839) plus rapamycin for patients with recurrent malignant glioma." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
130S
End Page
130S

Efficacy of imatinib mesylate plus hydroxyurea regimen in the treatment of recurrent malignant glioma: Phase II study results

Authors
Friedman, HS; Quinn, J; Rich, J; Vredenburgh, J; Desjardins, A; Sathornsumetee, S; Salvado, A; Nikolova, Z; Bigner, D; Reardon, D
MLA Citation
Friedman, HS, Quinn, J, Rich, J, Vredenburgh, J, Desjardins, A, Sathornsumetee, S, Salvado, A, Nikolova, Z, Bigner, D, and Reardon, D. "Efficacy of imatinib mesylate plus hydroxyurea regimen in the treatment of recurrent malignant glioma: Phase II study results." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
117S
End Page
117S

Results of a phase II study of 131 iodine-labeled anti-tenascin murine monoclonal antibody B1C6 (m81C6) administered to deliver a targeted radiation boost dose of 44 Gy to the surgically created cystic resection cavity perimeter in the treatment of patients with newly diagnosed primary and metastatic brain tumors

Authors
Vredenburgh, JJ; Reardon, D; Akabani, G; Friedman, A; Friedman, H; McLendon, R; Quinn, J; Rich, J; Zalutsky, M; Bigner, D
MLA Citation
Vredenburgh, JJ, Reardon, D, Akabani, G, Friedman, A, Friedman, H, McLendon, R, Quinn, J, Rich, J, Zalutsky, M, and Bigner, D. "Results of a phase II study of 131 iodine-labeled anti-tenascin murine monoclonal antibody B1C6 (m81C6) administered to deliver a targeted radiation boost dose of 44 Gy to the surgically created cystic resection cavity perimeter in the treatment of patients with newly diagnosed primary and metastatic brain tumors." June 1, 2005.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
23
Issue
16
Publish Date
2005
Start Page
116S
End Page
116S

Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant gliomas: a phase II study.

UNLABELLED: The objective was to perform dosimetry and evaluate dose-response relationships in newly diagnosed patients with malignant brain tumors treated with direct injections of (131)I-labeled anti-tenascin murine 81C6 monoclonal antibody (mAb) into surgically created resection cavities (SCRCs) followed by conventional external-beam radiotherapy and chemotherapy. METHODS: Absorbed doses to the 2-cm-thick shell, measured from the margins of the resection cavity interface, were estimated for 33 patients with primary brain tumors. MRI/SPECT registrations were used to assess the distribution of the radiolabeled mAb in brain parenchyma. Results from biopsies obtained from 15 patients were classified as tumor, radionecrosis, or tumor and radionecrosis, and these were correlated with absorbed dose and dose rate. Also, MRI/PET registrations were used to assess radiographic progression among patients. RESULTS: This therapeutic strategy yielded a median survival of 86 and 79 wk for all patients and glioblastoma multiforme (GBM) patients, respectively. The average SCRC residence time of (131)I-mu81C6 mAb was 76 h (range, 34-169 h). The average absorbed dose to the 2-cm cavity margins was 48 Gy (range, 25-116 Gy) for all patients and 51 Gy (range, 27-116 Gy) for GBM patients. In MRI/SPECT registrations, we observed a preferential distribution of (131)I-mu81C6 mAb through regions of vasogenic edema. An analysis of the relationship between the absorbed dose and dose rate and the first biopsy results yielded a most favorable absorbed dose of 44 Gy. A correlation between decreased survival and irreversible neurotoxicity was noted. A comparative analysis, in terms of median survival, was performed with previous brachytherapy clinical studies, which showed a proportional relationship between the average boost absorbed dose and the median survival. CONCLUSION: This study shows that (131)I-mu81C6 mAb increases the median survival of GBM patients. An optimal absorbed dose of 44 Gy to the 2-cm cavity margins is suggested to reduce the incidence of neurologic toxicity. Further clinical studies are warranted to determine the effectiveness of (131)I-mu81C6 mAb based on a target dose of 44 Gy rather than a fixed administered activity.

Authors
Akabani, G; Reardon, DA; Coleman, RE; Wong, TZ; Metzler, SD; Bowsher, JE; Barboriak, DP; Provenzale, JM; Greer, KL; DeLong, D; Friedman, HS; Friedman, AH; Zhao, X-G; Pegram, CN; McLendon, RE; Bigner, DD; Zalutsky, MR
MLA Citation
Akabani, G, Reardon, DA, Coleman, RE, Wong, TZ, Metzler, SD, Bowsher, JE, Barboriak, DP, Provenzale, JM, Greer, KL, DeLong, D, Friedman, HS, Friedman, AH, Zhao, X-G, Pegram, CN, McLendon, RE, Bigner, DD, and Zalutsky, MR. "Dosimetry and radiographic analysis of 131I-labeled anti-tenascin 81C6 murine monoclonal antibody in newly diagnosed patients with malignant gliomas: a phase II study." J Nucl Med 46.6 (June 2005): 1042-1051.
PMID
15937318
Source
pubmed
Published In
Journal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume
46
Issue
6
Publish Date
2005
Start Page
1042
End Page
1051

Gene expression profiling and genetic markers in glioblastoma survival.

Despite the strikingly grave prognosis for older patients with glioblastomas, significant variability in patient outcome is experienced. To explore the potential for developing improved prognostic capabilities based on the elucidation of potential biological relationships, we did analyses of genes commonly mutated, amplified, or deleted in glioblastomas and DNA microarray gene expression data from tumors of glioblastoma patients of age >50 for whom survival is known. No prognostic significance was associated with genetic changes in epidermal growth factor receptor (amplified in 17 of 41 patients), TP53 (mutated in 11 of 41 patients), p16INK4A (deleted in 15 of 33 patients), or phosphatase and tensin homologue (mutated in 15 of 41 patients). Statistical analysis of the gene expression data in connection with survival involved exploration of regression models on small subsets of genes, based on computational search over multiple regression models with cross-validation to assess predictive validity. The analysis generated a set of regression models that, when weighted and combined according to posterior probabilities implied by the statistical analysis, identify patterns in expression of a small subset of genes that are associated with survival and have value in assessing survival risks. The dominant genes across such multiple regression models involve three key genes-SPARC (Osteonectin), Doublecortex, and Semaphorin3B-which play key roles in cellular migration processes. Additional analysis, based on statistical graphical association models constructed using similar computational analysis methods, reveals other genes which support the view that multiple mediators of tumor invasion may be important prognostic factor in glioblastomas in older patients.

Authors
Rich, JN; Hans, C; Jones, B; Iversen, ES; McLendon, RE; Rasheed, BKA; Dobra, A; Dressman, HK; Bigner, DD; Nevins, JR; West, M
MLA Citation
Rich, JN, Hans, C, Jones, B, Iversen, ES, McLendon, RE, Rasheed, BKA, Dobra, A, Dressman, HK, Bigner, DD, Nevins, JR, and West, M. "Gene expression profiling and genetic markers in glioblastoma survival." Cancer Res 65.10 (May 15, 2005): 4051-4058.
PMID
15899794
Source
pubmed
Published In
Cancer Research
Volume
65
Issue
10
Publish Date
2005
Start Page
4051
End Page
4058
DOI
10.1158/0008-5472.CAN-04-3936

Methods and outcomes for recruitment of cases and controls for a brain tumor epidemiology study.

Authors
Lyons, P; Davis, F; Bigner, D; Friedman, H; McCarthy, B; Rauscher, G; Vick, N; Paleologos, N; Tourt-Uhlig, S; Lada, P
MLA Citation
Lyons, P, Davis, F, Bigner, D, Friedman, H, McCarthy, B, Rauscher, G, Vick, N, Paleologos, N, Tourt-Uhlig, S, and Lada, P. "Methods and outcomes for recruitment of cases and controls for a brain tumor epidemiology study." ONCOLOGY NURSING FORUM 32.2 (March 2005): 484-484.
Source
wos-lite
Published In
Oncology Nursing Forum
Volume
32
Issue
2
Publish Date
2005
Start Page
484
End Page
484

Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid.

Through digital karyotyping of permanent medulloblastoma cell lines, we found that the homeobox gene OTX2 was amplified more than 10-fold in three cell lines. Gene expression analyses showed that OTX2 transcripts were present at high levels in 14 of 15 (93%) medulloblastomas with anaplastic histopathologic features. Knockdown of OTX2 expression by siRNAs inhibited medulloblastoma cell growth in vitro, whereas pharmacologic doses of all-trans retinoic acid repressed OTX2 expression and induced apoptosis only in medulloblastoma cell lines that expressed OTX2. These observations suggest that OTX2 is essential for the pathogenesis of anaplastic medulloblastomas and that these tumors may be amenable to therapy with all-trans-retinoic acid.

Authors
Di, C; Liao, S; Adamson, DC; Parrett, TJ; Broderick, DK; Shi, Q; Lengauer, C; Cummins, JM; Velculescu, VE; Fults, DW; McLendon, RE; Bigner, DD; Yan, H
MLA Citation
Di, C, Liao, S, Adamson, DC, Parrett, TJ, Broderick, DK, Shi, Q, Lengauer, C, Cummins, JM, Velculescu, VE, Fults, DW, McLendon, RE, Bigner, DD, and Yan, H. "Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid." Cancer Res 65.3 (February 1, 2005): 919-924.
PMID
15705891
Source
pubmed
Published In
Cancer Research
Volume
65
Issue
3
Publish Date
2005
Start Page
919
End Page
924

Sustained radiographic and clinical response in patient with bifrontal recurrent glioblastoma multiforme with intracerebral infusion of the recombinant targeted toxin TP-38: case study.

Glioblastoma multiforme remains refractory to conventional therapy, and novel therapeutic modalities are desperately needed. TP-38 is a recombinant chimeric protein containing a genetically engineered form of the cytotoxic Pseudomonas exotoxin fused to transforming growth factor (TGF)-alpha. TGF-alpha binds with high affinity to the epidermal growth factor receptor, which is uniformly overexpressed in malignant gliomas, often because of gene amplification. Prior to therapy with TP-38, the patient described here was completely refractory to multiple other therapies, with radiographic and pathologic evidence of tumor progression. After therapy, she improved clinically, was weaned off steroids and anti-convulsants, and experienced a progressive decrease in enhancing tumor volume. Despite multiple prior recurrences, she has not progressed for >43 months after TP-38 therapy. Small remaining areas of enhancement demonstrate no evidence of tumor histologically and are hypometabolic on positron emission tomography. This report describes a dramatic and sustained clinical and radiographic response in a patient with a bifrontal glioblastoma multiforme treated with intratumoral infusion of a novel targeted toxin, TP-38.

Authors
Sampson, JH; Reardon, DA; Friedman, AH; Friedman, HS; Coleman, RE; McLendon, RE; Pastan, I; Bigner, DD
MLA Citation
Sampson, JH, Reardon, DA, Friedman, AH, Friedman, HS, Coleman, RE, McLendon, RE, Pastan, I, and Bigner, DD. "Sustained radiographic and clinical response in patient with bifrontal recurrent glioblastoma multiforme with intracerebral infusion of the recombinant targeted toxin TP-38: case study." Neuro Oncol 7.1 (January 2005): 90-96.
PMID
15701286
Source
pubmed
Published In
Neuro-Oncology
Volume
7
Issue
1
Publish Date
2005
Start Page
90
End Page
96
DOI
10.1215/S1152851703000589

Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition.

Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a single molecular target may slow tumor progression, but tumors are likely not dependent on a signal transduction pathway. Rather, malignant gliomas exhibit sustained mitogenesis and cell growth mediated in part through the effects of receptor tyrosine kinases and the mammalian target of rapamycin (mTOR). AEE788 is a novel orally active tyrosine kinase inhibitor that decreases the kinase activity associated with the epidermal growth factor receptor and, at higher concentrations, the vascular endothelial growth factor receptor 2 (kinase domain region). RAD001 (everolimus) is an orally available mTOR inhibitor structurally related to rapamycin. We hypothesized that combined inhibition of upstream epidermal growth factor receptor and kinase domain region receptors with AEE788 and inhibition of the downstream mTOR pathway with RAD001 would result in increased efficacy against gliomas compared with single-agent therapy. In vitro experiments showed that the combination of AEE788 and RAD001 resulted in increased rates of cell cycle arrest and apoptosis and reduced proliferation more than either agent alone. Combined AEE788 and RAD001 given orally to athymic mice bearing established human malignant glioma tumor xenografts resulted in greater tumor growth inhibition and greater increases in median survival than monotherapy. These studies suggest that simultaneous inhibition of growth factor receptor and mTOR pathways offer increased benefit in glioma therapy.

Authors
Goudar, RK; Shi, Q; Hjelmeland, MD; Keir, ST; McLendon, RE; Wikstrand, CJ; Reese, ED; Conrad, CA; Traxler, P; Lane, HA; Reardon, DA; Cavenee, WK; Wang, X-F; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Goudar, RK, Shi, Q, Hjelmeland, MD, Keir, ST, McLendon, RE, Wikstrand, CJ, Reese, ED, Conrad, CA, Traxler, P, Lane, HA, Reardon, DA, Cavenee, WK, Wang, X-F, Bigner, DD, Friedman, HS, and Rich, JN. "Combination therapy of inhibitors of epidermal growth factor receptor/vascular endothelial growth factor receptor 2 (AEE788) and the mammalian target of rapamycin (RAD001) offers improved glioblastoma tumor growth inhibition." Mol Cancer Ther 4.1 (January 2005): 101-112.
PMID
15657358
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
4
Issue
1
Publish Date
2005
Start Page
101
End Page
112

Neuro-Oncology impact factor for 2004

Authors
Bigner, DD; James, CD; Cohn, SA
MLA Citation
Bigner, DD, James, CD, and Cohn, SA. "Neuro-Oncology impact factor for 2004." Neuro-Oncology 7.4 (2005): 423-424.
Source
scival
Published In
Neuro-Oncology
Volume
7
Issue
4
Publish Date
2005
Start Page
423
End Page
424
DOI
10.1215/S1152851705200066

Tenascin-C, over expressed in lung cancer down regulates effector functions of tumor infiltrating lymphocytes

Purpose: Extracellular matrix (ECM) proteins play a significant role in the survival and metastasis of cancer cells. Tenascin-C (TN-C) is an extracellular matrix protein and its large isoform has been implicated in tumor progression. Goal of this study was to analyze the expression of the small and large isoforms of TN-C in non-small cell lung cancer (NSCLC) and determine its functional significance. Experimental design: TN-C expression was studied in tumor and non-tumor tissue of patients with NSCLC at the mRNA and protein level. Immunomodulatory properties of the large isoform of TN-C were analyzed by determining its effect on lymphocyte proliferation and cytokine secretion by tumor-infiltrating lymphocytes (TIL). Results: Quantitative real-time PCR analysis showed an eight-fold increase in the amount of large isoform in cancer cells compared to adjacent normal tissue. Expression at the protein level by Western blot analysis using a murine monoclonal anti-TN-C antibody detected increased expression of the large isoform in the tumor tissue that was correlated with the development of recurrent disease. A 18-fold increase in the expression of the large TN-C isoform was observed in patients with recurrent NSCLC compared to non-recurrent NSCLC. Large isoform of TN-C significantly inhibited anti-CD3 and mitogen-induced proliferation of human peripheral blood lymphocytes and interferon-gamma production by TIL isolated from the lung cancer specimens. Conclusions: Increased expression of TN-C observed at the site of tumor in NSCLC correlates with recurrence. TN-C inhibits TIL proliferation and cytokine thereby may promote tumor immune evasion and recurrence. © 2004 Elsevier Ireland Ltd. All rights reserved.

Authors
Parekh, K; Ramachandran, S; Cooper, J; Bigner, D; Patterson, A; Mohanakumar, T
MLA Citation
Parekh, K, Ramachandran, S, Cooper, J, Bigner, D, Patterson, A, and Mohanakumar, T. "Tenascin-C, over expressed in lung cancer down regulates effector functions of tumor infiltrating lymphocytes." Lung Cancer 47.1 (2005): 17-29.
PMID
15603851
Source
scival
Published In
Lung Cancer
Volume
47
Issue
1
Publish Date
2005
Start Page
17
End Page
29
DOI
10.1016/j.lungcan.2004.05.016

Secreted protein acidic, rich in cysteine (SPARC), mediates cellular survival of gliomas through AKT activation.

Secreted protein acidic, rich in cysteine (SPARC), is an extracellular matrix protein expressed in many advanced cancers, including malignant gliomas. We and others have previously shown that human glioma cell lines engineered to overexpress SPARC adopt an invasive phenotype. We now show that SPARC expression increases cell survival under stress initiated by serum withdrawal through a decrease in apoptosis. Phosphatidylinositol 3-OH kinase/AKT is a potent pro-survival pathway that contributes to the malignancy of gliomas. Cells expressing SPARC display increased AKT activation with decreased caspase 3/7 activity. Exogenous SPARC rapidly induces AKT phosphorylation, an effect that is blocked by a neutralizing SPARC antibody. Furthermore, AKT activation is essential for the anti-apoptotic effects of SPARC as the decreased apoptosis and caspase activity associated with SPARC expression can be blocked with dominant-negative AKT or a specific AKT inhibitor. As tumor cells face stressful microenvironments particularly during the process of invasion, these results suggest that SPARC functions, in part, to promote tumor progression by enabling tumor cells to survive under stressful conditions.

Authors
Shi, Q; Bao, S; Maxwell, JA; Reese, ED; Friedman, HS; Bigner, DD; Wang, X-F; Rich, JN
MLA Citation
Shi, Q, Bao, S, Maxwell, JA, Reese, ED, Friedman, HS, Bigner, DD, Wang, X-F, and Rich, JN. "Secreted protein acidic, rich in cysteine (SPARC), mediates cellular survival of gliomas through AKT activation." J Biol Chem 279.50 (December 10, 2004): 52200-52209.
PMID
15469933
Source
pubmed
Published In
The Journal of biological chemistry
Volume
279
Issue
50
Publish Date
2004
Start Page
52200
End Page
52209
DOI
10.1074/jbc.M409630200

Evaluation of an internalizing monoclonal antibody labeled using N-succinimidyl 3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), a negatively charged substituent bearing acylation agent.

Monoclonal antibodies such as L8A4, reactive with the epidermal growth factor receptor variant III, internalize after receptor binding resulting in proteolytic degradation by lysosomes. Labeling internalizing mAbs requires the use of methodologies that result in the trapping of labeled catabolites in tumor cells after intracellular processing. Herein we have investigated the potential utility of N-succinimidyl-3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), an acylation agent that couples the corresponding negatively charged acid [131I]IPMBA to the protein, for this purpose. Biodistribution studies demonstrated that [131I]IPMBA cleared rapidly from normal tissues and exhibited thyroid levels < or =0.1% injected dose, consistent with a low degree of dehalogenation. Biodistribution experiments in athymic mice bearing subcutaneous D-256 human glioma xenografts were performed to compare L8A4 labeled using [131I]SIPMB to L8A4 labeled with 125I using both the analogous positively charged acylation agent N-succinimidyl-4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB) and Iodogen. Tumor uptake of [131I]SIPMB-L8A4 (41.9+/-3.5% ID/g) was nearly threefold that of L8A4 labeled using Iodogen (14.0+/-1.1% ID/g) after 2 days, and tumor to tissue ratios remained uniformly high throughout with [131I]SIPMB-L8A4. Thyroid uptake increased for the Iodogen labeled mAb (3.55+/-0.36 %ID at 5 days) whereas that of [131I]SIPMB labeled mAb remained low (0.21+/-0.04% ID at 5 days). In the second biodistribution, L8A4 labeled using [131I]SIPMB and [125I]SGMIB showed no difference in normal tissue uptake and had nearly identical tumor uptake ([131I]SIPMB, 41.8+/-14.2% ID/g; [125I]SGMIB, 41.6+/-15.8% ID/g, at 4 days). These results suggest that [131I]SIPMB may be a viable acylation agent for the radioiodination of internalizing mAbs.

Authors
Shankar, S; Vaidyanathan, G; Affleck, DJ; Peixoto, K; Bigner, DD; Zalutsky, MR
MLA Citation
Shankar, S, Vaidyanathan, G, Affleck, DJ, Peixoto, K, Bigner, DD, and Zalutsky, MR. "Evaluation of an internalizing monoclonal antibody labeled using N-succinimidyl 3-[131I]iodo-4-phosphonomethylbenzoate ([131I]SIPMB), a negatively charged substituent bearing acylation agent." Nucl Med Biol 31.7 (October 2004): 909-919.
PMID
15464393
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
31
Issue
7
Publish Date
2004
Start Page
909
End Page
919
DOI
10.1016/j.nucmedbio.2004.04.007

Medulloblastoma neoplastic meningitis targeted radiotherapy with intrathecal alpha-emitter At-211-labeled thymidine analogue

Authors
Boskovitz, A; Vaidyanathan, G; Archer, GE; Ochiai, H; Okamura, T; Sampson, JH; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, Vaidyanathan, G, Archer, GE, Ochiai, H, Okamura, T, Sampson, JH, Bigner, DD, and Zalutsky, MR. "Medulloblastoma neoplastic meningitis targeted radiotherapy with intrathecal alpha-emitter At-211-labeled thymidine analogue." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
403
End Page
403

Dendritic cell vaccine for intracranial tumors I (DC Victori trial)

Authors
Archer, GE; Bigner, D; Friedman, A; Friedman, H; Penne, K; Lally-Batts, D; Paolino, A; Tourt-Uhlig, S; Reardon, D; Sampson, J
MLA Citation
Archer, GE, Bigner, D, Friedman, A, Friedman, H, Penne, K, Lally-Batts, D, Paolino, A, Tourt-Uhlig, S, Reardon, D, and Sampson, J. "Dendritic cell vaccine for intracranial tumors I (DC Victori trial)." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
341
End Page
341

Monoclonal antibodies (MABS) against somatostatin receptor 2A (SSTR2A) as potential medulloblastoma therapeutic reagents

Authors
Kuan, CT; Wikstrand, CJ; Davis, TS; Zalutsky, MR; Bigner, DD
MLA Citation
Kuan, CT, Wikstrand, CJ, Davis, TS, Zalutsky, MR, and Bigner, DD. "Monoclonal antibodies (MABS) against somatostatin receptor 2A (SSTR2A) as potential medulloblastoma therapeutic reagents." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
409
End Page
409

Detection and immunologic recognition of cytomegalovirus antigens expressed within malignant gliomas

Authors
Mitchell, DA; Learn, C; Schmittling, R; Friedman, A; McLendon, RE; Bigner, DD; Sampson, JH
MLA Citation
Mitchell, DA, Learn, C, Schmittling, R, Friedman, A, McLendon, RE, Bigner, DD, and Sampson, JH. "Detection and immunologic recognition of cytomegalovirus antigens expressed within malignant gliomas." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
343
End Page
343

Inhibition of receptor tyrosine kinases and mammalian target of rapamycin offers combinatorial benefit in tumor control

Authors
Gondar, RK; Hjelmeland, MD; Keir, ST; Conrad, CA; McLendon, RE; Wikstrand, CJ; Traxler, P; Lane, HA; Reardon, DA; Cavenee, WK; Wang, XF; Bigner, DD; Friedman, HS; Rich, JN
MLA Citation
Gondar, RK, Hjelmeland, MD, Keir, ST, Conrad, CA, McLendon, RE, Wikstrand, CJ, Traxler, P, Lane, HA, Reardon, DA, Cavenee, WK, Wang, XF, Bigner, DD, Friedman, HS, and Rich, JN. "Inhibition of receptor tyrosine kinases and mammalian target of rapamycin offers combinatorial benefit in tumor control." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
407
End Page
407

SB-431542, a small molecule transforming growth factor-B-receptor antagonist, inhibits human glioma cell line proliferation and motility

Authors
Hjelmeland, M; Hjelmeland, A; Sathornsumetee, S; Herbstreith, MH; Laping, NJ; Bigner, DD; Wang, XF; Rich, JN
MLA Citation
Hjelmeland, M, Hjelmeland, A, Sathornsumetee, S, Herbstreith, MH, Laping, NJ, Bigner, DD, Wang, XF, and Rich, JN. "SB-431542, a small molecule transforming growth factor-B-receptor antagonist, inhibits human glioma cell line proliferation and motility." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
408
End Page
408

Phase II study of 131-iodine-labeled anti-tenascin murine monoclonal antibody 81C6 (M81C6) administered to deliver a targeted radiation boost dose of 44 Gy to the surgically created cystic resection cavity perimeter in the treatment of patients with newly diagnosed primary and metastatic brain tumors

Authors
Reardon, D; Akabani, G; Friedman, A; Friedman, H; Herndon, J; McLendon, R; Quinn, J; Rich, J; Vredenburgh, J; Penne, K; Sampson, J; Gururangan, S; Shafman, T; Wong, T; Dowell, J; Dunn, R; Badruddoja, M; Desjardins, A; Affronti, M; Allen, D; Jackson, S; Zeigler, K; Silverman, S; Tourt-Uhlig, S; Coleman, R; Zalutsky, N; Bigner, D
MLA Citation
Reardon, D, Akabani, G, Friedman, A, Friedman, H, Herndon, J, McLendon, R, Quinn, J, Rich, J, Vredenburgh, J, Penne, K, Sampson, J, Gururangan, S, Shafman, T, Wong, T, Dowell, J, Dunn, R, Badruddoja, M, Desjardins, A, Affronti, M, Allen, D, Jackson, S, Zeigler, K, Silverman, S, Tourt-Uhlig, S, Coleman, R, Zalutsky, N, and Bigner, D. "Phase II study of 131-iodine-labeled anti-tenascin murine monoclonal antibody 81C6 (M81C6) administered to deliver a targeted radiation boost dose of 44 Gy to the surgically created cystic resection cavity perimeter in the treatment of patients with newly diagnosed primary and metastatic brain tumors." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
381
End Page
381

Phase II trial of imatinib mesylate plus hydroxyurea in the treatment of patients with malignant glioma

Authors
Reardon, D; Friedman, A; Herndon, J; Quinn, J; Rich, J; Vredenburgh, J; Badruddoja, M; Desjardins, A; Sampson, J; Gururangan, S; Dowell, J; Affronti, M; Allen, D; Jackson, S; Zeigler, K; Silverman, S; Tourt-Uhlig, S; Silverman, S; Salvado, A; Nikolova, Z; Bigner, D; Friedman, H
MLA Citation
Reardon, D, Friedman, A, Herndon, J, Quinn, J, Rich, J, Vredenburgh, J, Badruddoja, M, Desjardins, A, Sampson, J, Gururangan, S, Dowell, J, Affronti, M, Allen, D, Jackson, S, Zeigler, K, Silverman, S, Tourt-Uhlig, S, Silverman, S, Salvado, A, Nikolova, Z, Bigner, D, and Friedman, H. "Phase II trial of imatinib mesylate plus hydroxyurea in the treatment of patients with malignant glioma." October 2004.
Source
wos-lite
Published In
Neuro-Oncology
Volume
6
Issue
4
Publish Date
2004
Start Page
381
End Page
381

Monoclonal antibodies for brain tumour treatment.

Conventional treatment of brain tumours includes surgical, radiotherapeutic and chemotherapeutic modalities. Nonetheless, the outcome of patients with brain tumours, in particular glioblastoma, remains poor. Immunotherapy with armed or unarmed monoclonal antibodies targeting tumour-specific antigens has emerged in the last two decades as a novel potential adjuvant treatment for all types of neoplasia. Many challenges to its implementation as a safe and viable therapy for brain tumours still need to be addressed; nevertheless, results from ongoing Phase I/II clinical trials are encouraging, as disease stabilisation and patient survival prolongation have been observed. Advances in preclinical and clinical research indicate that treatment of brain tumours with monoclonal antibodies can be increasingly adjusted to the characteristics of the targeted tumour and its environment. This aspect relies on the careful selection of the target antigen and corresponding specific monoclonal antibody, and antibody format (size, class, affinity), conjugation to the appropriate toxin or radioactive isotope (half-life, range), and proper compartmental administration.

Authors
Boskovitz, A; Wikstrand, CJ; Kuan, C-T; Zalutsky, MR; Reardon, DA; Bigner, DD
MLA Citation
Boskovitz, A, Wikstrand, CJ, Kuan, C-T, Zalutsky, MR, Reardon, DA, and Bigner, DD. "Monoclonal antibodies for brain tumour treatment." Expert Opin Biol Ther 4.9 (September 2004): 1453-1471. (Review)
PMID
15335313
Source
pubmed
Published In
Expert Opinion on Biological Therapy
Volume
4
Issue
9
Publish Date
2004
Start Page
1453
End Page
1471
DOI
10.1517/14712598.4.9.1453

Brain tumor cell lines resistant to O6-benzylguanine/1,3-bis(2-chloroethyl)-1-nitrosourea chemotherapy have O6-alkylguanine-DNA alkyltransferase mutations.

The chemotherapeutic activity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU or carmustine) may be improved by the addition of O6-benzylguanine (O6-BG). The reaction of O6-BG with O6-alkylguanine-DNA alkyltransferase (AGT) prevents the repair of O6-chloroethyl lesions caused by BCNU. In clinics, the combination of O6-BG and BCNU is now being tested for the treatment of brain tumors. However, the effectiveness of this drug regimen may be limited by drug resistance acquired during treatment. To understand the possible mechanisms of resistance of brain tumor cells to the O6-BG/BCNU combination, we generated medulloblastoma cell lines (D283 MED, D341 MED, and Daoy) resistant to the combination of O6-BG and BCNU [O6-BG/BCNU resistant (OBR)]. DNA sequencing showed that all of the parent cell lines express wild-type AGTs, whereas every OBR cell line exhibited mutations that potentially affected the binding of O6-BG to the protein as evidenced previously by in vitro mutagenesis and structural studies of AGT. The D283 MED (OBR), Daoy (OBR), and D341 MED (OBR) cell lines expressed G156C, Y114F, and K165T AGT mutations, respectively. We reported previously that rhabdomyosarcoma TE-671 (OBR) also expresses a G156C mutation. These data suggest that the clonal selection of AGT mutants during treatment with O6-BG plus an alkylator may produce resistance to this intervention in clinical settings.

Authors
Bacolod, MD; Johnson, SP; Pegg, AE; Dolan, ME; Moschel, RC; Bullock, NS; Fang, Q; Colvin, OM; Modrich, P; Bigner, DD; Friedman, HS
MLA Citation
Bacolod, MD, Johnson, SP, Pegg, AE, Dolan, ME, Moschel, RC, Bullock, NS, Fang, Q, Colvin, OM, Modrich, P, Bigner, DD, and Friedman, HS. "Brain tumor cell lines resistant to O6-benzylguanine/1,3-bis(2-chloroethyl)-1-nitrosourea chemotherapy have O6-alkylguanine-DNA alkyltransferase mutations." Mol Cancer Ther 3.9 (September 2004): 1127-1135.
PMID
15367707
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
3
Issue
9
Publish Date
2004
Start Page
1127
End Page
1135

Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma.

We report a phase 1 study of pharmacokinetics, dosimetry, toxicity, and response of (131)I anti-tenascin chimeric 81C6 for the treatment of lymphoma. Nine patients received a dosimetric dose of 370 MBq (10 mCi). Three patients received an administered activity of 1480 MBq (40 mCi), and 2 developed hematologic toxicity that required stem cell infusion. Six patients received an administered activity of 1110 MBq (30 mCi), and 2 developed toxicity that required stem cell infusion. The clearance of whole-body activity was monoexponential with a mean effective half-life of 110 hours (range, 90-136 hours) and a mean effective whole-body residence time of 159 hours (range, 130-196 hours). There was rapid uptake within the viscera; however, tumor uptake was slower. Activity in normal viscera decreased proportional to the whole body; however, tumor sites presented a slow clearance (T(1/2), 86-191 hours). The mean absorbed dose to whole-body was 67 cGy (range, 51-89 hours), whereas the dose to tumor sites was 963 cGy (range, 363-1517 cGy). Despite lack of a "blocking" antibody, 1 of 9 patients attained a complete remission and 1 a partial remission. These data demonstrate this radiopharmaceutical to be an encouraging agent for the treatment of lymphoma particularly if methods to protect the normal viscera are developed.

Authors
Rizzieri, DA; Akabani, G; Zalutsky, MR; Coleman, RE; Metzler, SD; Bowsher, JE; Toaso, B; Anderson, E; Lagoo, A; Clayton, S; Pegram, CN; Moore, JO; Gockerman, JP; DeCastro, C; Gasparetto, C; Chao, NJ; Bigner, DD
MLA Citation
Rizzieri, DA, Akabani, G, Zalutsky, MR, Coleman, RE, Metzler, SD, Bowsher, JE, Toaso, B, Anderson, E, Lagoo, A, Clayton, S, Pegram, CN, Moore, JO, Gockerman, JP, DeCastro, C, Gasparetto, C, Chao, NJ, and Bigner, DD. "Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma." Blood 104.3 (August 1, 2004): 642-648.
PMID
15100153
Source
pubmed
Published In
Blood
Volume
104
Issue
3
Publish Date
2004
Start Page
642
End Page
648
DOI
10.1182/blood-2003-12-4264

Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas.

The phosphatidylinositol 3'-kinase pathway is activated in multiple advanced cancers, including glioblastomas, through inactivation of the PTEN tumor suppressor gene. Recently, mutations in PIK3CA, a member of the family of phosphatidylinositol 3'-kinase catalytic subunits, were identified in a significant fraction (25-30%) of colorectal cancers, gastric cancers, and glioblastomas and in a smaller fraction of breast and lung cancers. These mutations were found to cluster into two major "hot spots" located in the helical and catalytic domains. To determine whether PIK3CA is genetically altered in brain tumors, we performed a large-scale mutational analysis of the helical and catalytic domains. A total of 13 mutations of PIK3CA within these specific domains were identified in anaplastic oligodendrogliomas, anaplastic astrocytomas, glioblastoma multiforme, and medulloblastomas, whereas no mutations were identified in ependymomas or low-grade astrocytomas. These observations implicate PIK3CA as an oncogene in a wider spectrum of adult and pediatric brain tumors and suggest that PIK3CA may be a useful diagnostic marker or a therapeutic target in these cancers.

Authors
Broderick, DK; Di, C; Parrett, TJ; Samuels, YR; Cummins, JM; McLendon, RE; Fults, DW; Velculescu, VE; Bigner, DD; Yan, H
MLA Citation
Broderick, DK, Di, C, Parrett, TJ, Samuels, YR, Cummins, JM, McLendon, RE, Fults, DW, Velculescu, VE, Bigner, DD, and Yan, H. "Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas." Cancer Res 64.15 (August 1, 2004): 5048-5050.
PMID
15289301
Source
pubmed
Published In
Cancer Research
Volume
64
Issue
15
Publish Date
2004
Start Page
5048
End Page
5050
DOI
10.1158/0008-5472.CAN-04-1170

Comparative genomic hybridization analysis of astrocytomas: prognostic and diagnostic implications.

Astrocytoma is comprised of a group of common intracranial neoplasms that are classified into four grades based on the World Health Organization histological criteria and patient survival. To date, histological grade, patient age, and clinical performance, as reflected in the Karnofsky score, are the most reliable prognostic predictors. Recently, there has been a significant effort to identify additional prognostic markers using objective molecular genetic techniques. We believe that the identification of such markers will characterize new chromosomal loci important in astrocytoma progression and aid clinical diagnosis and prognosis. To this end, our laboratory used comparative genomic hybridization to identify DNA sequence copy number changes in 102 astrocytomas. Novel losses of 19p loci were detected in low-grade pilocytic astrocytomas and losses of loci on 9p, 10, and 22 along with gains on 7, 19, and 20 were detected in a significant proportion of high-grade astrocytomas. The Cox proportional hazards statistical modeling showed that the presence of +7q and -10q comparative genomic hybridization alterations significantly increased a patient's risk of dying, independent of histological grade. This investigation demonstrates the efficacy of comparative genomic hybridization for identifying tumor suppressor and oncogene loci in different astrocytic grades. The cumulative effect of these loci is an important consideration in their diagnostic and prognostic implications.

Authors
Wiltshire, RN; Herndon, JE; Lloyd, A; Friedman, HS; Bigner, DD; Bigner, SH; McLendon, RE
MLA Citation
Wiltshire, RN, Herndon, JE, Lloyd, A, Friedman, HS, Bigner, DD, Bigner, SH, and McLendon, RE. "Comparative genomic hybridization analysis of astrocytomas: prognostic and diagnostic implications." J Mol Diagn 6.3 (August 2004): 166-179.
PMID
15269292
Source
pubmed
Published In
The Journal of molecular diagnostics : JMD
Volume
6
Issue
3
Publish Date
2004
Start Page
166
End Page
179
DOI
10.1016/S1525-1578(10)60507-7

Phase I trial study of [131]I-labeled chimeric 81C6 mAb for the treatment of patients with non-Hodgkin's lymphoma

Authors
Akabani, G; Rizzieri, DA; Zalutsky, MR; Coleman, RE; Metzler, SD; Bowsher, JE; Toaso, B; Lagoo, A; Moore, JO; Gockerman, JP; DeCastro, C; Gasparetto, C; Chao, NJ; Bigner, DD
MLA Citation
Akabani, G, Rizzieri, DA, Zalutsky, MR, Coleman, RE, Metzler, SD, Bowsher, JE, Toaso, B, Lagoo, A, Moore, JO, Gockerman, JP, DeCastro, C, Gasparetto, C, Chao, NJ, and Bigner, DD. "Phase I trial study of [131]I-labeled chimeric 81C6 mAb for the treatment of patients with non-Hodgkin's lymphoma." August 2004.
Source
wos-lite
Published In
European Journal of Nuclear Medicine and Molecular Imaging
Volume
31
Publish Date
2004
Start Page
S222
End Page
S222

Erlotinib HCL for glioblastoma multiforme in first relapse, a phase II trial.

Authors
Yung, A; Vredenburgh, J; Cloughesy, T; Klencke, BJ; Mischel, PS; Bigner, DD; Aldape, K; Vanderburg, S; Prados, M
MLA Citation
Yung, A, Vredenburgh, J, Cloughesy, T, Klencke, BJ, Mischel, PS, Bigner, DD, Aldape, K, Vanderburg, S, and Prados, M. "Erlotinib HCL for glioblastoma multiforme in first relapse, a phase II trial." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
120S
End Page
120S

Phase II trial of iodine 131-labeled murine anti-tenascin monoclonal anti-body 81C6 (M81C6) via surgically created resection cavity in the treatment of patients with recurrent malignant brain tumors.

Authors
Badruddoja, MA; Reardon, DA; Akabani, G; Friedman, AH; Friedman, HS; Rich, JN; Quinn, JA; Penne, K; Vredenburgh, JJ; Bigner, DD
MLA Citation
Badruddoja, MA, Reardon, DA, Akabani, G, Friedman, AH, Friedman, HS, Rich, JN, Quinn, JA, Penne, K, Vredenburgh, JJ, and Bigner, DD. "Phase II trial of iodine 131-labeled murine anti-tenascin monoclonal anti-body 81C6 (M81C6) via surgically created resection cavity in the treatment of patients with recurrent malignant brain tumors." July 15, 2004.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
22
Issue
14
Publish Date
2004
Start Page
124S
End Page
124S

Erlotinib HCL for glioblastoma multiforme in first relapse, a phase II trial.

1555 Background: Erlotinib HCL (Tarceva), an orally active, highly potent and selective inhibitor of the epidermal growth factor receptor (HER1/EGFR), has documented clinical activity in glioblastoma multiforme (GBM) (M Prados ASCO 02). GBM is an interesting target for EGFR inhibitors because of the high rate of EGFR gene amplification and activating mutations in EGFR (i.e. EGFRvIII).A multi-institutional phase II clinical trial of the single agent Tarceva was initiated in August 2003 for GBM patients with measurable disease in first relapse. Tarceva is metabolized by CYP3A4, therefore to ensure adequate exposure patients receiving enzyme-inducing anti-epileptic drugs (EIAED group) receive a higher starting dose (300mg/d), otherwise standard dose of 150mg/d was given (non-EIAED group) Individual dose titration until dose-limiting toxicity (diarrhea, rash, other) was allowed, from 150 to 200mg (non-EIAED group) or from 300 to 500mg in 50-mg increments (EIAED group).Forty-eight subjects (19 female, 29 male) with a median age of 50 years (37-70) have been enrolled to date. 21 on concurrent EIAEDs; 27 received 150mg/d initially. 23 of the 48 subjects have been able to dose escalate at least once, 2 are now receiving 450 or 500mg, and 1 discontinued therapy on day 10 due to skin toxicity at their 300mg/d starting dose. Pharmacokinetic measurements are being obtained in this study. At week 8, 1 subject had a CR, 1 subject achieved PR (unconfirmed), 11 had stable disease (SD) although 4 of the SD subjects have subsequently progressed. To date, 27 patients have progressed and 1 is not evaluable. Gene amplification, as determined by FISH, has been seen in 16 of 30 subjects.These preliminary data suggest that erlotinib is active in recurrent GBM. Updated results, including the association between EGFR status, including gene amplification status, IHC expression, and EGFRvIII status, will be presented. [Table: see text].

Authors
Yung, A; Vredenburgh, J; Cloughesy, T; Klencke, BJ; Mischel, PS; Bigner, DD; Aldape, K; Vanderburg, S; Prados, M
MLA Citation
Yung, A, Vredenburgh, J, Cloughesy, T, Klencke, BJ, Mischel, PS, Bigner, DD, Aldape, K, Vanderburg, S, and Prados, M. "Erlotinib HCL for glioblastoma multiforme in first relapse, a phase II trial." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 1555-.
PMID
28015448
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
1555

Phase II trial of iodine 131-labeled murine anti-tenascin monoclonal anti-body 81C6 (M81C6) via surgically created resection cavity in the treatment of patients with recurrent malignant brain tumors.

1569 Background: In a prior phase I study we established the dose of 100mCi as the maximum tolerated dose of iodine 131-labeled murine anti-tenascin antibody 81C6 (131I-81C6) injected into a surgically created resection cavity (SCRC) for the treatment of recurrent malignant glioma in adult patients.In the current phase II study we have treated 42 patients with recurrent brain tumors (GBM=32, AA=6, AO=2, infiltrating glioma = 1, metastatic =1). Patients were included into study if they had: 1) gross total resection, 2) KPS > 60%, 3) normal bone marrow and normal hepatic and renal function. All patients had received standard external beam radiation and 14 (33%) patients had received prior chemotherapy.The median age was 54.5 years and 27 patients (64%) were males. All patients received 100mCi except for two patients that received 67mCi and 75mCi respectively due to the limited size of the SCRC. Toxicities were divided into acute (< 4 weeks), subacute (4-16 weeks) and delayed (>16 weeks) periods. Acute and sub-acute reversible, grade 4 hematologic toxicity was seen in 2 patients (4%) and 3 (7%) patients, respectively. Delayed grade 3 or 4 neurotoxicity was seen in 2 patients (4%). The median survival of all patients and GBM patients was 59 weeks for both groups, respectively. For patients with GBM the probability of 1-year survival is 0.56 (CI-95%; 0.41-0.78). As of December 16, 2003, 15 patients remain alive with a median follow up of 81.9 weeks for GBMs and 78.9 weeks for all patients.I131- labeled murine anti-tenascin antibody 81C6 is associated with minimal hematologic toxicity and provides an improvement in survival in patients with recurrent malignant glioma that have failed conventional therapy. No significant financial relationships to disclose.

Authors
Badruddoja, MA; Reardon, DA; Akabani, G; Friedman, AH; Friedman, HS; Rich, JN; Quinn, JA; Penne, K; Vredenburgh, JJ; Bigner, DD
MLA Citation
Badruddoja, MA, Reardon, DA, Akabani, G, Friedman, AH, Friedman, HS, Rich, JN, Quinn, JA, Penne, K, Vredenburgh, JJ, and Bigner, DD. "Phase II trial of iodine 131-labeled murine anti-tenascin monoclonal anti-body 81C6 (M81C6) via surgically created resection cavity in the treatment of patients with recurrent malignant brain tumors." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 22.14_suppl (July 2004): 1569-.
PMID
28015735
Source
epmc
Published In
Journal of Clinical Oncology
Volume
22
Issue
14_suppl
Publish Date
2004
Start Page
1569

Poliovirus receptor CD155-targeted oncolysis of glioma.

Cell adhesion molecules of the immunoglobulin superfamily are aberrantly expressed in malignant glioma. Amongst these, the human poliovirus receptor CD155 provides a molecular target for therapeutic intervention with oncolytic poliovirus recombinants. Poliovirus has been genetically modified through insertion of regulatory sequences derived from human rhinovirus type 2 to selectively replicate within and destroy cancerous cells. Efficacious oncolysis mediated by poliovirus derivatives depends on the presence of CD155 in targeted tumors. To prepare oncolytic polioviruses for clinical application, we have developed a series of assays in high-grade malignant glioma (HGL) to characterize CD155 expression levels and susceptibility to oncolytic poliovirus recombinants. Analysis of 6 HGL cases indicates that CD155 is expressed in these tumors and in primary cell lines derived from these tumors. Upregulation of the molecular target CD155 rendered explant cultures of all studied tumors highly susceptible to a prototype oncolytic poliovirus recombinant. Our observations support the clinical application of such agents against HGL.

Authors
Merrill, MK; Bernhardt, G; Sampson, JH; Wikstrand, CJ; Bigner, DD; Gromeier, M
MLA Citation
Merrill, MK, Bernhardt, G, Sampson, JH, Wikstrand, CJ, Bigner, DD, and Gromeier, M. "Poliovirus receptor CD155-targeted oncolysis of glioma." Neuro Oncol 6.3 (July 2004): 208-217.
PMID
15279713
Source
pubmed
Published In
Neuro-Oncology
Volume
6
Issue
3
Publish Date
2004
Start Page
208
End Page
217
DOI
10.1215/S1152851703000577

SB-431542, a small molecule transforming growth factor-beta-receptor antagonist, inhibits human glioma cell line proliferation and motility.

Transforming growth factor-beta (TGF-beta) is a multifunctional cytokine that promotes malignant glioma invasion, angiogenesis, and immunosuppression. Antisense oligonucleotide suppression of TGF-beta(2) ligand expression has shown promise in preclinical and clinical studies but at least two ligands mediate the effects of TGF-beta in gliomas. Therefore, we examined the effects of SB-431542, a novel, small molecule inhibitor of the type I TGF-beta receptor, on a panel of human malignant glioma cell lines. SB-431542 blocked the phosphorylation and nuclear translocation of the SMADs, intracellular mediators of TGF-beta signaling, with decreased TGF-beta-mediated transcription. Furthermore, SB-431542 inhibited the expression of two critical effectors of TGF-beta-vascular endothelial growth factor and plasminogen activator inhibitor-1. SB-431542 treatment of glioma cultures inhibited proliferation, TGF-beta-mediated morphologic changes, and cellular motility. Together, our results suggest that small molecule inhibitors of TGF-beta receptors may offer a novel therapy for malignant gliomas by reducing cell proliferation, angiogenesis, and motility.

Authors
Hjelmeland, MD; Hjelmeland, AB; Sathornsumetee, S; Reese, ED; Herbstreith, MH; Laping, NJ; Friedman, HS; Bigner, DD; Wang, X-F; Rich, JN
MLA Citation
Hjelmeland, MD, Hjelmeland, AB, Sathornsumetee, S, Reese, ED, Herbstreith, MH, Laping, NJ, Friedman, HS, Bigner, DD, Wang, X-F, and Rich, JN. "SB-431542, a small molecule transforming growth factor-beta-receptor antagonist, inhibits human glioma cell line proliferation and motility." Mol Cancer Ther 3.6 (June 2004): 737-745.
PMID
15210860
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
3
Issue
6
Publish Date
2004
Start Page
737
End Page
745

Resistance to tyrosine kinase inhibition by mutant epidermal growth factor receptor variant III contributes to the neoplastic phenotype of glioblastoma multiforme.

PURPOSE: We have reported previously that tumors expressing wild-type epidermal growth factor receptor (EGFR) in a murine model are sensitive to the EGFR tyrosine kinase inhibitor gefitinib, whereas tumors expressing mutant EGFR variant III (EGFRvIII) are resistant. Determination of how this differential inhibition occurs may be important to patient selection and treatment criteria, as well as the design of future therapeutics for glioblastoma multiforme. EXPERIMENTAL DESIGN: We have determined and quantified how treatment with gefitinib at commonly used, noncytotoxic doses affects neoplastic functions ascribed to EGFRvIII, including downstream signaling by Akt, DNA synthesis, and cellular invasion. In doing so, we have tested and compared a series of wild-type and mutant EGFRvIII-expressing fibroblast and glioblastoma cell lines in vitro after treatment with gefitinib. RESULTS: The results of these experiments demonstrate that short-term treatment with gefitinib (approximately 24 h) does not reduce phosphorylation of EGFRvIII, whereas EGFR phosphorylation is inhibited in a dose-dependent manner. However, after daily treatment with gefitinib, phosphorylation declines for EGFRvIII by day 3 and later. Nevertheless, after 7 days of daily treatment, cells that express and are dependent on EGFRvIII for tumorigenic growth are not effectively growth inhibited. This may be due in part to phosphorylation of Akt, which is inhibited in EGFR-expressing cells after treatment with gefitinib, but is unaffected in cells expressing EGFRvIII. Cell cycle analysis shows that nascent DNA synthesis in EGFR-expressing cells is inhibited in a dose-dependent manner by gefitinib, yet is unaffected in EGFRvIII-expressing cells with increasing dosage. Furthermore, cells expressing EGFRvIII demonstrate greater invasive capability with increasing gefitinib concentration when compared with cells expressing EGFR after treatment. CONCLUSIONS: We conclude that the neoplastic phenotype of EGFRvIII is relatively resistant to gefitinib and requires higher doses, repeated dosing, and longer exposure to decrease receptor phosphorylation. However, this decrease does not effectively inhibit the biologically relevant processes of DNA synthesis, cellular growth, and invasion in cells expressing EGFRvIII.

Authors
Learn, CA; Hartzell, TL; Wikstrand, CJ; Archer, GE; Rich, JN; Friedman, AH; Friedman, HS; Bigner, DD; Sampson, JH
MLA Citation
Learn, CA, Hartzell, TL, Wikstrand, CJ, Archer, GE, Rich, JN, Friedman, AH, Friedman, HS, Bigner, DD, and Sampson, JH. "Resistance to tyrosine kinase inhibition by mutant epidermal growth factor receptor variant III contributes to the neoplastic phenotype of glioblastoma multiforme." Clin Cancer Res 10.9 (May 1, 2004): 3216-3224.
PMID
15131063
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
10
Issue
9
Publish Date
2004
Start Page
3216
End Page
3224

Development of novel targeted therapies in the treatment of malignant glioma.

Authors
Rich, JN; Bigner, DD
MLA Citation
Rich, JN, and Bigner, DD. "Development of novel targeted therapies in the treatment of malignant glioma." Nat Rev Drug Discov 3.5 (May 2004): 430-446. (Review)
PMID
15136790
Source
pubmed
Published In
Nature Reviews Drug Discovery
Volume
3
Issue
5
Publish Date
2004
Start Page
430
End Page
446
DOI
10.1038/nrd1380

Human/murine chimeric 81C6 F(ab')(2) fragment: preclinical evaluation of a potential construct for the targeted radiotherapy of malignant glioma.

We have obtained encouraging responses in recent Phase I studies evaluating (131)I-labeled human/murine chimeric 81C6 anti-tenascin monoclonal antibody (ch81C6) administered into surgically-created tumor resection cavities in brain tumor patients. However, because the blood clearance is slow, hematologic toxicity has been higher than seen with murine 81C6 (mu81C6). In the current study, a series of paired-label experiments were performed in athymic mice bearing subcutaneous D-245 MG human glioma xenografts to compare the biodistribution of the fragment ch81C6 F(ab')(2) labeled using Iodogen to a) intact ch81C6, b) mu81C6, and c) ch81C6 F(ab')(2) labeled using N-succinimidyl 3-[(131)I]iodobenzoate. Tumor retention of radioiodine activity for the F(ab')(2) fragment was comparable to that for intact ch81C6 for the first 24 h and to that for mu81C6 for the first 48 h; as expected, blood and other normal tissue levels declined faster for ch81C6 F(ab')(2.) Radiation dosimetry calculations suggest that (131)I-labeled ch81C6 F(ab')(2) may warrant further evaluation as a targeted radiotherapeutic for the treatment of brain tumors.

Authors
Boskovitz, A; Akabani, GH; Pegram, CN; Bigner, DD; Zalutsky, MR
MLA Citation
Boskovitz, A, Akabani, GH, Pegram, CN, Bigner, DD, and Zalutsky, MR. "Human/murine chimeric 81C6 F(ab')(2) fragment: preclinical evaluation of a potential construct for the targeted radiotherapy of malignant glioma." Nucl Med Biol 31.3 (April 2004): 345-355.
PMID
15028247
Source
pubmed
Published In
Nuclear Medicine and Biology
Volume
31
Issue
3
Publish Date
2004
Start Page
345
End Page
355
DOI
10.1016/j.nucmedbio.2003.10.008

Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma.

Irinotecan is a topoisomerase I inhibitor previously shown to be active in the treatment of malignant glioma. We now report the results of a phase 1 trial of irinotecan plus BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, for patients with recurrent or progressive MG. Irinotecan dose escalation occurred independently within 2 strata: patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and patients not receiving EIAEDs. BCNU was administered at a dose of 100 mg/m2 over 1 h every 6 weeks on the same day as the first irinotecan dose was administered. Irinotecan was administered intravenously over 90 min once weekly. Treatment cycles consisted of 4 weekly administrations of irinotecan followed by a 2-week rest with dose escalation in cohorts of 3 to 6 patients. Seventy-three patients were treated, including 49 patients who were on EIAEDs and 24 who were not on EIAEDs. The maximum tolerated dose for patients not on EIAEDs was 125 mg/m2. The maximum tolerated dose for patients on EIAEDs was 225 mg/m2. Dose-limiting toxicity was evenly distributed among the following organ systems: pulmonary, gastrointestinal, cardiovascular, neurologic, infectious, and hematologic, without a clear predominance of toxicity involving any one organ system. There was no evidence of increasing incidence of toxicity involving one organ system as irinotecan dose was escalated. On the basis of these results, we conclude that the recommended doses of irinotecan for a phase 2 clinical trial when given in combination with BCNU (100 mg/m2) are 225 mg/m2 for patients on EIAEDs and 125 mg/m2 for patients not on EIAEDs.

Authors
Quinn, JA; Reardon, DA; Friedman, AH; Rich, JN; Sampson, JH; Vredenburgh, J; Gururangan, S; Provenzale, JM; Walker, A; Schweitzer, H; Bigner, DD; Tourt-Uhlig, S; Herndon, JE; Affronti, ML; Jackson, S; Allen, D; Ziegler, K; Bohlin, C; Lentz, C; Friedman, HS
MLA Citation
Quinn, JA, Reardon, DA, Friedman, AH, Rich, JN, Sampson, JH, Vredenburgh, J, Gururangan, S, Provenzale, JM, Walker, A, Schweitzer, H, Bigner, DD, Tourt-Uhlig, S, Herndon, JE, Affronti, ML, Jackson, S, Allen, D, Ziegler, K, Bohlin, C, Lentz, C, and Friedman, HS. "Phase 1 trial of irinotecan plus BCNU in patients with progressive or recurrent malignant glioma." Neuro Oncol 6.2 (April 2004): 145-153.
PMID
15134629
Source
pubmed
Published In
Neuro-Oncology
Volume
6
Issue
2
Publish Date
2004
Start Page
145
End Page
153
DOI
10.1215/S1152851703000498

Phase 2 trial of BCNU plus irinotecan in adults with malignant glioma.

In preclinical studies, BCNU, or 1,3-bis(2-chloroethyl)-1-nitrosourea, plus CPT-11 (irinotecan) exhibits schedule-dependent, synergistic activity against malignant glioma (MG). We previously established the maximum tolerated dose of CPT-11 when administered for 4 consecutive weeks in combination with BCNU administered on the first day of each 6-week cycle. We now report a phase 2 trial of BCNU plus CPT-11 for patients with MG. In the current study, BCNU (100 mg/m2) was administered on day 1 of each 6-week cycle. CPT-11 was administered on days 1, 8, 15, and 22 at 225 mg/m2 for patients receiving CYP3A1- or CYP3A4-inducing anticonvulsants and at 125 mg/m2 for those not on these medications. Newly diagnosed patients received up to 3 cycles before radiotherapy, while recurrent patients received up to 8 cycles. The primary end point of this study was radiographic response, while time to progression and overall survival were also assessed. Seventy-six patients were treated, including 37 with newly diagnosed tumors and 39 with recurrent disease. Fifty-six had glioblastoma multiforme, 18 had anaplastic astrocytoma, and 2 had anaplastic oligodendroglioma. Toxicities (grade > or =3) included infections (13%), thromboses (12%), diarrhea (10%), and neutropenia (7%). Interstitial pneumonitis developed in 4 patients. Five newly diagnosed patients (14%; 95% CI, 5%-29%) achieved a radiographic response (1 complete response and 4 partial responses). Five patients with recurrent MG also achieved a response (1 complete response and 4 partial responses; 13%; 95% CI, 4%-27%). More than 40% of both newly diagnosed and recurrent patients achieved stable disease. Median time to progression was 11.3 weeks for recurrent glioblastoma multiforme patients and 16.9 weeks for recurrent anaplastic astrocytoma/ anaplastic oligodendroglioma patients. We conclude that the activity of BCNU plus CPT-11 for patients with MG appears comparable to that of CPT-11 alone and may be more toxic.

Authors
Reardon, DA; Quinn, JA; Rich, JN; Gururangan, S; Vredenburgh, J; Sampson, JH; Provenzale, JM; Walker, A; Badruddoja, M; Tourt-Uhlig, S; Herndon, JE; Dowell, JM; Affronti, ML; Jackson, S; Allen, D; Ziegler, K; Silverman, S; Bohlin, C; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Reardon, DA, Quinn, JA, Rich, JN, Gururangan, S, Vredenburgh, J, Sampson, JH, Provenzale, JM, Walker, A, Badruddoja, M, Tourt-Uhlig, S, Herndon, JE, Dowell, JM, Affronti, ML, Jackson, S, Allen, D, Ziegler, K, Silverman, S, Bohlin, C, Friedman, AH, Bigner, DD, and Friedman, HS. "Phase 2 trial of BCNU plus irinotecan in adults with malignant glioma." Neuro Oncol 6.2 (April 2004): 134-144.
PMID
15134628
Source
pubmed
Published In
Neuro-Oncology
Volume
6
Issue
2
Publish Date
2004
Start Page
134
End Page
144

Phase II trial of gefitinib in recurrent glioblastoma.

PURPOSE: To evaluate the efficacy and tolerability of gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE), a novel epidermal growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. PATIENTS AND METHODS: This was an open-label, single-center phase II trial. Fifty-seven patients with first recurrence of a glioblastoma who were previously treated with surgical resection, radiation, and usually chemotherapy underwent an open biopsy or resection at evaluation for confirmation of tumor recurrence. Each patient initially received 500 mg of gefitinib orally once daily; dose escalation to 750 mg then 1,000 mg, if a patient received enzyme-inducing antiepileptic drugs or dexamethasone, was allowed within each patient. RESULTS: Although no objective tumor responses were seen among the 53 assessable patients, only 21% of patients (11 of 53 patients) had measurable disease at treatment initiation. Seventeen percent of patients (nine of 53 patients) underwent at least six 4-week cycles, and the 6-month event-free survival (EFS) was 13% (seven of 53 patients). The median EFS time was 8.1 weeks, and the median overall survival (OS) time from treatment initiation was 39.4 weeks. Adverse events were generally mild (grade 1 or 2) and consisted mainly of skin reactions and diarrhea. Drug-related toxicities were more frequent at higher doses. Withdrawal caused by drug-related adverse events occurred in 6% of patients (three of 53 patients). Although the presence of diarrhea positively predicted favorable OS from treatment initiation, epidermal growth factor receptor expression did not correlate with either EFS or OS. CONCLUSION: Gefitinib is well tolerated and has activity in patients with recurrent glioblastoma. Further study of this agent at higher doses is warranted.

Authors
Rich, JN; Reardon, DA; Peery, T; Dowell, JM; Quinn, JA; Penne, KL; Wikstrand, CJ; Van Duyn, LB; Dancey, JE; McLendon, RE; Kao, JC; Stenzel, TT; Ahmed Rasheed, BK; Tourt-Uhlig, SE; Herndon, JE; Vredenburgh, JJ; Sampson, JH; Friedman, AH; Bigner, DD; Friedman, HS
MLA Citation
Rich, JN, Reardon, DA, Peery, T, Dowell, JM, Quinn, JA, Penne, KL, Wikstrand, CJ, Van Duyn, LB, Dancey, JE, McLendon, RE, Kao, JC, Stenzel, TT, Ahmed Rasheed, BK, Tourt-Uhlig, SE, Herndon, JE, Vredenburgh, JJ, Sampson, JH, Friedman, AH, Bigner, DD, and Friedman, HS. "Phase II trial of gefitinib in recurrent glioblastoma." J Clin Oncol 22.1 (January 1, 2004): 133-142.
PMID
14638850
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
22
Issue
1
Publish Date
2004
Start Page
133
End Page
142
DOI
10.1200/JCO.2004.08.110

Consistency of primary brain tumor diagnoses and codes in cancer surveillance systems.

High-quality cancer registry data are essential for assessing trends in incidence rates. This study evaluated the consistency of brain tumor surveillance data using a random sample of cases from the Connecticut Tumor Registry. Three neuropathologists independently and blindly reviewed tumor slides from 204 cases and a nosologist blindly reviewed and assigned International Classification of Diseases for Oncology (ICD-O) codes to 326 cases. For the pathology review, absolute concordance was as high as 81% for all primary brain tumors. Absolute concordance rates were high for nerve sheath (89%), meningioma (95%), and pituitary (95%) tumors. Rates were much lower for malignant tumors. ICD-O coding of malignant brain tumors is of relatively high quality with the exception of mixed gliomas and unspecified tumors. A high level of consistency for nonmalignant brain tumor diagnoses suggests that rates for these tumors, when actively reported to a surveillance system, can be of high quality.

Authors
Castillo, MS; Davis, FG; Surawicz, T; Bruner, JM; Bigner, S; Coons, S; Bigner, DD
MLA Citation
Castillo, MS, Davis, FG, Surawicz, T, Bruner, JM, Bigner, S, Coons, S, and Bigner, DD. "Consistency of primary brain tumor diagnoses and codes in cancer surveillance systems." Neuroepidemiology 23.1-2 (January 2004): 85-93.
PMID
14739573
Source
pubmed
Published In
Neuroepidemiology
Volume
23
Issue
1-2
Publish Date
2004
Start Page
85
End Page
93
DOI
10.1159/000073980

Immune responses of breast cancer patients to mutated epidermal growth factor receptor (EGF-RvIII, ΔEGF-R, and de2-7 EGF-R)

Mutated epidermal growth factor receptor (EGF-RvIII, ΔEGF-R, and de2-7 EGF-R) is the result of an 801-bp deletion within the extracellular domain of wild-type EGF-R and is expressed by breast carcinomas, but not by normal breast tissues. EGF-RvIII is expressed both on the surface and in the cytoplasm of tumor cells. Thus, EGF-RvIII is a potential tumor-specific target for both Abs and T cells. However, it is not known whether breast cancer patients can raise immune responses to EGF-RvIII expressed by their tumors. The demonstration of EGF-RvIII-speciflc immune responses in patients would suggest that immunization of patients with EGF-RvIII vaccines is feasible, because these vaccines may boost a pre-existing immune response. We have evaluated humoral and cellular immune responses to EGF-RvIII in 16 breast cancer patients and three healthy donors. Seven of 16 patients developed EGF-RvIII-specific Abs that bound to isolated EGF-RvIII protein or the protein expressed by EGF-RvIII-transfected mouse fibroblasts. The Abs that bound to EGF-RvIII did not bind to wild-type EGF-R, and anti-EGF-RvIII Abs were not found in the sera of healthy donors. Three patients had EGF-RvIII peptide-specific lymphoproliferative responses, and two of these patients also had humoral immune responses. Humoral and cellular immune responses correlated with EGF-RvIII expression by patients' tumors in most cases. These studies demonstrate that breast cancer patients specifically recognize EGF-RvIII with an overall immune response rate of 50%, suggesting that patients may benefit from vaccination against EGF-RvIII, boosting pre-existing immune responses.

Authors
Purey, E; Cai, D; Miller, E; Swoboda, R; Mayer, T; Klein-Szanto, A; Marincola, FM; Mick, R; Otvos, L; Wunner, W; Birebent, B; Somasundaram, R; Wikstrand, CJ; Bigner, D; DeMichele, A; Acs, G; Berlin, JA; Herlyn, D
MLA Citation
Purey, E, Cai, D, Miller, E, Swoboda, R, Mayer, T, Klein-Szanto, A, Marincola, FM, Mick, R, Otvos, L, Wunner, W, Birebent, B, Somasundaram, R, Wikstrand, CJ, Bigner, D, DeMichele, A, Acs, G, Berlin, JA, and Herlyn, D. "Immune responses of breast cancer patients to mutated epidermal growth factor receptor (EGF-RvIII, ΔEGF-R, and de2-7 EGF-R)." Journal of Immunology 173.10 (2004): 6472-6480.
PMID
15528389
Source
scival
Published In
Journal of Immunology
Volume
173
Issue
10
Publish Date
2004
Start Page
6472
End Page
6480

Editorial

Authors
Bigner, DD; James, CD; Cohn, SA
MLA Citat