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Becher, Oren Josh

Overview:

My laboratory interests are to apply genetic mouse models of pediatric brain tumors to prioritize the translation of novel agents into clinical trials. In particular, my laboratory is using a genetic mouse model of Diffuse Intrinsic Pontine Gliomas to determine therapeutic targets, mechanisms of resistance to targeted agents, unravel new ways to bypass the blood-brain-barrier, and investigate region-specific differences between gliomagenesis in the brainstem and the cortex. My laboratory is also developing improved genetic mouse models of Diffuse Intrinsic Pontine Glioma (DIPG).

Positions:

Associate Professor of Pediatrics

Pediatrics, Hematology-Oncology
School of Medicine

Assistant Professor in Pathology

Pathology
School of Medicine

Assistant Professor in Pharmacology and Cancer Biology

Pharmacology & Cancer Biology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 2000

M.D. — Johns Hopkins University School of Medicine

Pediatric Internship And Residency, Pediatrics

Children's Hospital National Medical Center

Pediatric Hematoloty Oncology Fellowship, Pediatrics

Memorial Hospital for Cancer

Pediatric Neuro Oncology Fellowship, Pediatrics

Memorial Hospital for Cancer

Grants:

Functional Dissection of the K27M Histone Mutation In Gliomagenesis

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
August 05, 2016
End Date
July 31, 2021

Pharmacological Sciences Training Program

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
Participating Faculty Member
Start Date
July 01, 1975
End Date
June 30, 2020

Functional Dissection of the K27M Histone Mutation in Vivo

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 01, 2014
End Date
August 31, 2019

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

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

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

The role of H3K27M-induced aberrant PRC2 activity in brainstem gliomagenesis

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
September 29, 2015
End Date
September 28, 2017

Optimizing the Convection Enhanced Delivery of Targeted Agents for Midline Gliomas

Administered By
Neurosurgery
AwardedBy
Southeastern Brain Tumor Foundation
Role
Investigator
Start Date
July 01, 2016
End Date
June 30, 2017

Regional differences in Central Nervous System Gliomagenesis

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Damon Runyon Cancer Research Foundation
Role
Principal Investigator
Start Date
July 01, 2015
End Date
June 30, 2017

Pediatric Brain Tumor Consortium

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
St. Jude Children's Research Hospital
Role
Co-Principal Investigator
Start Date
April 01, 2014
End Date
March 31, 2017

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

Identifying novel drugs for the treatment of brainstem tumours by direct infusion into the brain

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Abbie's Army
Role
Principal Investigator
Start Date
August 01, 2015
End Date
July 31, 2016

Evaluation of Olig2 inhibitors in a genetically engineered mouse model of DIPG

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Curtana Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
March 25, 2015
End Date
March 25, 2016

Dissection of H3.3-K27's role in radiation resistance in DIPG

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
Joshua's Wish, Inc.
Role
Principal Investigator
Start Date
June 01, 2015
End Date
August 31, 2015

Development of peptide vaccine for diffuse intrinsic pontine glioma

Administered By
Pediatrics, Hematology-Oncology
AwardedBy
The Cure Starts Now
Role
Principal Investigator
Start Date
November 01, 2013
End Date
October 31, 2014
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Publications:

A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: Long-term progression-free survival of patients with resistant neuroblastoma.

AKT plays a pivotal role in driving the malignant phenotype of many cancers, including high-risk neuroblastoma (HR-NB). AKT signaling, however, is active in normal tissues, raising concern about excessive toxicity from its suppression. The oral AKT inhibitor perifosine showed tolerable toxicity in adults and in our phase I trial in children with solid tumors (clinicaltrials.gov NCT00776867). We now report on the HR-NB experience. HR-NB patients received perifosine 50-75 mg m(-2)  day(-1) after a loading dose of 100-200 mg m(-2) on day 1, and continued on study until progressive disease. The 27 HR-NB patients included three treated for primary refractory disease and 24 with disease resistant to salvage therapy after 1-5 (median 2) relapses; only one had MYCN-amplified HR-NB. Pharmacokinetic studies showed μM concentrations consistent with cytotoxic levels in preclinical models. Nine patients (all MYCN-non-amplified) remained progression-free through 43+ to 74+ (median 54+) months from study entry, including the sole patient to show a complete response and eight patients who had persistence of abnormal (123) I-metaiodobenzylguanidine skeletal uptake but never developed progressive disease. Toxicity was negligible in all 27 patients, even with the prolonged treatment (11-62 months, median 38) in the nine long-term progression-free survivors. The clinical findings (i) confirm the safety of therapeutic serum levels of an AKT inhibitor in children; (ii) support perifosine for MYCN-non-amplified HR-NB as monotherapy after completion of standard treatment or combined with other agents (based on preclinical studies) to maximize antitumor effects; and (iii) highlight the welcome possibility that refractory or relapsed MYCN-non-amplified HR-NB is potentially curable.

Authors
Kushner, BH; Cheung, NV; Modak, S; Becher, OJ; Basu, EM; Roberts, SS; Kramer, K; Dunkel, IJ
MLA Citation
Kushner, BH, Cheung, NV, Modak, S, Becher, OJ, Basu, EM, Roberts, SS, Kramer, K, and Dunkel, IJ. "A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: Long-term progression-free survival of patients with resistant neuroblastoma." International journal of cancer 140.2 (January 2017): 480-484.
PMID
27649927
Source
epmc
Published In
International Journal of Cancer
Volume
140
Issue
2
Publish Date
2017
Start Page
480
End Page
484
DOI
10.1002/ijc.30440

Diffuse Intrinsic Pontine Glioma: Time for Cautious Optimism.

Diffuse intrinsic pontine glioma is a lethal brain cancer that arises in the pons of children. The median survival for children with diffuse intrinsic pontine glioma is less than 1 year from diagnosis, and no improvement in survival has been realized in more than 30 years. Currently, the standard of care for diffuse intrinsic pontine glioma is focal radiation therapy, which provides only temporary relief. Recent genomic analysis of tumors from biopsies and autopsies, have resulted in the discovery of K27M H3.3/H3.1 mutations in 80% and ACVR1 mutations in 25% of diffuse intrinsic pontine gliomas, providing renewed hope for future success in identifying effective therapies. In addition, as stereotactic tumor biopsies at diagnosis at specialized centers have been demonstrated to be safe, biopsies have now been incorporated into several prospective clinical trials. This article summarizes the epidemiology, clinical presentation, diagnosis, prognosis, molecular genetics, current treatment, and future therapeutic directions for diffuse intrinsic pontine glioma.

Authors
Hennika, T; Becher, OJ
MLA Citation
Hennika, T, and Becher, OJ. "Diffuse Intrinsic Pontine Glioma: Time for Cautious Optimism." Journal of child neurology 31.12 (October 2016): 1377-1385.
PMID
26374787
Source
epmc
Published In
Journal of Child Neurology
Volume
31
Issue
12
Publish Date
2016
Start Page
1377
End Page
1385
DOI
10.1177/0883073815601495

Pediatric high-grade glioma: biologically and clinically in need of new thinking.

High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace. It is important to avoid therapeutic strategies developed purely using data obtained from studies on adult glioblastoma. This approach has resulted in repetitive trials and ineffective treatments being applied to these children, with limited improvement in clinical outcome. The authors of this perspective, comprising biology and clinical expertise in the disease, recently convened to discuss the most effective ways to translate the emerging molecular insights into patient benefit. This article reviews our current understanding of pediatric high-grade glioma and suggests approaches for innovative clinical management.

Authors
Jones, C; Karajannis, MA; Jones, DT; Kieran, MW; Monje, M; Baker, SJ; Becher, OJ; Cho, YJ; Gupta, N; Hawkins, C; Hargrave, D; Haas-Kogan, DA; Jabado, N; Li, XN; Mueller, S; Nicolaides, T; Packer, RJ; Persson, AI; Phillips, JJ; Simonds, EF; Stafford, JM; Tang, Y; Pfister, SM; Weiss, WA
MLA Citation
Jones, C, Karajannis, MA, Jones, DT, Kieran, MW, Monje, M, Baker, SJ, Becher, OJ, Cho, YJ, Gupta, N, Hawkins, C, Hargrave, D, Haas-Kogan, DA, Jabado, N, Li, XN, Mueller, S, Nicolaides, T, Packer, RJ, Persson, AI, Phillips, JJ, Simonds, EF, Stafford, JM, Tang, Y, Pfister, SM, and Weiss, WA. "Pediatric high-grade glioma: biologically and clinically in need of new thinking." Neuro-oncology (June 9, 2016). (Review)
PMID
27282398
Source
epmc
Published In
Neuro-Oncology
Publish Date
2016

Pediatric Neuro-Oncology: Time to Go Molecular

Authors
Becher, OJ
MLA Citation
Becher, OJ. "Pediatric Neuro-Oncology: Time to Go Molecular." Oncology (Williston Park, N.Y.) 30.5 (May 1, 2016): 424-425.
Source
scopus
Published In
Oncology
Volume
30
Issue
5
Publish Date
2016
Start Page
424
End Page
425

ABCG2 and ABCB1 Limit the Efficacy of Dasatinib in a PDGF-B-Driven Brainstem Glioma Model.

Dasatinib is a multikinase inhibitor in clinical trials for glioma, and thus far has failed to demonstrate significant efficacy. We investigated whether the ABC efflux transporters ABCG2 and ABCB1 expressed in the blood-brain barrier (BBB), are limiting the efficacy of dasatinib in the treatment of glioma using genetic and pharmacologic approaches. We utilized a genetic brainstem glioma mouse model driven by platelet-derived growth factor-B and p53 loss using abcg2/abcb1 wild-type (ABC WT) or abcg2/abcb1 knockout mice (ABC KO). First, we observed that brainstem glioma tumor latency is significantly prolonged in ABC KO versus ABC WT mice (median survival of 47 vs. 34 days). Dasatinib treatment nearly doubles the survival of brainstem glioma-bearing ABC KO mice (44 vs. 80 days). Elacridar, an ABCG2 and ABCB1 inhibitor, significantly increases the efficacy of dasatinib in brainstem glioma-bearing ABC WT mice (42 vs. 59 days). Pharmacokinetic analysis demonstrates that dasatinib delivery into the normal brain, but not into the tumor core, is significantly increased in ABC KO mice compared with ABC WT mice. Surprisingly, elacridar did not significantly increase dasatinib delivery into the normal brain or the tumor core of ABC WT mice. Next, we demonstrate that the tight junctions of the BBB of this model are compromised as assessed by tissue permeability to Texas Red dextran. Finally, elacridar increases the cytotoxicity of dasatinib independent of ABCG2 and ABCB1 expression in vitro In conclusion, elacridar improves the efficacy of dasatinib in a brainstem glioma model without significantly increasing its delivery to the tumor core. Mol Cancer Ther; 15(5); 819-29. ©2016 AACR.

Authors
Mittapalli, RK; Chung, AH; Parrish, KE; Crabtree, D; Halvorson, KG; Hu, G; Elmquist, WF; Becher, OJ
MLA Citation
Mittapalli, RK, Chung, AH, Parrish, KE, Crabtree, D, Halvorson, KG, Hu, G, Elmquist, WF, and Becher, OJ. "ABCG2 and ABCB1 Limit the Efficacy of Dasatinib in a PDGF-B-Driven Brainstem Glioma Model." Molecular cancer therapeutics 15.5 (May 2016): 819-829.
PMID
26883271
Source
epmc
Published In
Molecular cancer therapeutics
Volume
15
Issue
5
Publish Date
2016
Start Page
819
End Page
829
DOI
10.1158/1535-7163.mct-15-0093

Pediatric Neuro-Oncology: Time to Go Molecular.

Authors
Becher, OJ
MLA Citation
Becher, OJ. "Pediatric Neuro-Oncology: Time to Go Molecular." Oncology (Williston Park, N.Y.) 30.5 (May 2016): 424-425.
PMID
27188672
Source
epmc
Published In
Oncology
Volume
30
Issue
5
Publish Date
2016
Start Page
424
End Page
425

Tumor location, but not H3.3K27M, significantly influences the blood-brain-barrier permeability in a genetic mouse model of pediatric high-grade glioma.

Pediatric high-grade gliomas (pHGGs) occur with strikingly different frequencies in infratentorial and supratentorial regions. Although histologically these malignancies appear similar, they represent distinct diseases. Recent genomic studies have identified histone K27M H3.3/H3.1 mutations in the majority of brainstem pHGGs; these mutations are rarely encountered in pHGGs that arise in the cerebral cortex. Previous research in brainstem pHGGs suggests a restricted permeability of the blood-brain-barrier (BBB). In this work, we use dynamic contrast-enhanced (DCE) MRI to evaluate BBB permeability in a genetic mouse model of pHGG as a function of location (cortex vs. brainstem, n = 8 mice/group) and histone mutation (mutant H3.3K27M vs. wild-type H3.3, n = 8 mice/group). The pHGG models are induced either in the brainstem or the cerebral cortex and are driven by PDGF signaling and p53 loss with either H3.3K27M or wild-type H3.3. T2-weighted MRI was used to determine tumor location/extent followed by 4D DCE-MRI for estimating the rate constant (K (trans) ) for tracer exchange across the barrier. BBB permeability was 67 % higher in cortical pHGGs relative to brainstem pHGGs (t test, p = 0.012) but was not significantly affected by the expression of mutant H3.3K27M versus wild-type H3.3 (t-test, p = 0.78). Although mice became symptomatic at approximately the same time, the mean volume of cortical tumors was 3.6 times higher than the mean volume of brainstem tumors. The difference between the mean volume of gliomas with wild-type and mutant H3.3 was insignificant. Mean K (trans) was significantly correlated to glioma volume. These results present a possible explanation for the poor response of brainstem pHGGs to systemic therapy. Our findings illustrate a potential role played by the microenvironment in shaping tumor growth and BBB permeability.

Authors
Subashi, E; Cordero, FJ; Halvorson, KG; Qi, Y; Nouls, JC; Becher, OJ; Johnson, GA
MLA Citation
Subashi, E, Cordero, FJ, Halvorson, KG, Qi, Y, Nouls, JC, Becher, OJ, and Johnson, GA. "Tumor location, but not H3.3K27M, significantly influences the blood-brain-barrier permeability in a genetic mouse model of pediatric high-grade glioma." Journal of neuro-oncology 126.2 (January 2016): 243-251.
PMID
26511492
Source
epmc
Published In
Journal of Neuro-Oncology
Volume
126
Issue
2
Publish Date
2016
Start Page
243
End Page
251
DOI
10.1007/s11060-015-1969-9

A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells.

Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises predominately in children and involves the pons, a structure that along with the midbrain and medulla makes up the brainstem. We have previously developed genetically engineered mouse models of brainstem glioma using the RCAS/Tv-a system by targeting PDGF-B overexpression, p53 loss, and H3.3K27M mutation to Nestin-expressing brainstem progenitor cells of the neonatal mouse. Here we describe a novel mouse model targeting these same genetic alterations to Pax3-expressing cells, which in the neonatal mouse pons consist of a Pax3+/Nestin+/Sox2+ population lining the fourth ventricle and a Pax3+/NeuN+ parenchymal population. Injection of RCAS-PDGF-B into the brainstem of Pax3-Tv-a mice at postnatal day 3 results in 40% of mice developing asymptomatic low-grade glioma. A mixture of low- and high-grade glioma results from injection of Pax3-Tv-a;p53(fl/fl) mice with RCAS-PDGF-B and RCAS-Cre, with or without RCAS-H3.3K27M. These tumors are Ki67+, Nestin+, Olig2+, and largely GFAP- and can arise anywhere within the brainstem, including the classic DIPG location of the ventral pons. Expression of the H3.3K27M mutation reduces overall H3K27me3 as compared with tumors without the mutation, similar to what has been previously shown in human and mouse tumors. Thus, we have generated a novel genetically engineered mouse model of DIPG, which faithfully recapitulates the human disease and represents a novel platform with which to study the biology and treatment of this deadly disease.

Authors
Misuraca, KL; Hu, G; Barton, KL; Chung, A; Becher, OJ
MLA Citation
Misuraca, KL, Hu, G, Barton, KL, Chung, A, and Becher, OJ. "A Novel Mouse Model of Diffuse Intrinsic Pontine Glioma Initiated in Pax3-Expressing Cells." Neoplasia (New York, N.Y.) 18.1 (January 2016): 60-70.
Website
http://hdl.handle.net/10161/12564
PMID
26806352
Source
epmc
Published In
Neoplasia (New York, N.Y.)
Volume
18
Issue
1
Publish Date
2016
Start Page
60
End Page
70
DOI
10.1016/j.neo.2015.12.002

Developing improved diffuse intrinsic pontine glioma mouse models

Authors
Becher, OJ
MLA Citation
Becher, OJ. "Developing improved diffuse intrinsic pontine glioma mouse models." December 1, 2015.
Source
wos-lite
Published In
Cancer Research
Volume
75
Publish Date
2015

Glioma Stem-like Cells Keep Their H3.3 Variant Levels at Bay.

Pediatric glioblastomas (GBMs) commonly harbor mutations in histone variant H3.3, while adult GBMs do not. In this issue of Cancer Cell, Gallo and colleagues demonstrate that adult GBM stem-like cells repress H3.3 expression to maintain self-renewal properties.

Authors
Becher, OJ; Holland, EC
MLA Citation
Becher, OJ, and Holland, EC. "Glioma Stem-like Cells Keep Their H3.3 Variant Levels at Bay." Cancer cell 28.6 (December 2015): 679-680.
PMID
26678332
Source
epmc
Published In
Cancer Cell
Volume
28
Issue
6
Publish Date
2015
Start Page
679
End Page
680
DOI
10.1016/j.ccell.2015.12.001

The emerging role of NG2 in pediatric diffuse intrinsic pontine glioma.

Diffuse intrinsic pontine gliomas (DIPGs) have a dismal prognosis and are poorly understood brain cancers. Receptor tyrosine kinases stabilized by neuron-glial antigen 2 (NG2) protein are known to induce gliomagenesis. Here, we investigated NG2 expression in a cohort of DIPG specimens (n= 50). We demonstrate NG2 expression in the majority of DIPG specimens tested and determine that tumors harboring histone 3.3 mutation express the highest NG2 levels. We further demonstrate that microRNA 129-2 (miR129-2) is downregulated and hypermethylated in human DIPGs, resulting in the increased expression of NG2. Treatment with 5-Azacytidine, a methyltransferase inhibitor, results in NG2 downregulation in DIPG primary tumor cells in vitro. NG2 expression is altered (symmetric segregation) in mitotic human DIPG and mouse tumor cells. These mitotic cells co-express oligodendrocyte (Olig2) and astrocyte (glial fibrillary acidic protein, GFAP) markers, indicating lack of terminal differentiation. NG2 knockdown retards cellular migration in vitro, while NG2 expressing neurospheres are highly tumorigenic in vivo, resulting in rapid growth of pontine tumors. NG2 expression is targetable in vivo using miR129-2 indicating a potential avenue for therapeutic interventions. This data implicates NG2 as a molecule of interest in DIPGs especially those with H3.3 mutation.

Authors
Yadavilli, S; Scafidi, J; Becher, OJ; Saratsis, AM; Hiner, RL; Kambhampati, M; Mariarita, S; MacDonald, TJ; Codispoti, KE; Magge, SN; Jaiswal, JK; Packer, RJ; Nazarian, J
MLA Citation
Yadavilli, S, Scafidi, J, Becher, OJ, Saratsis, AM, Hiner, RL, Kambhampati, M, Mariarita, S, MacDonald, TJ, Codispoti, KE, Magge, SN, Jaiswal, JK, Packer, RJ, and Nazarian, J. "The emerging role of NG2 in pediatric diffuse intrinsic pontine glioma." Oncotarget 6.14 (May 2015): 12141-12155.
PMID
25987129
Source
epmc
Published In
Oncotarget
Volume
6
Issue
14
Publish Date
2015
Start Page
12141
End Page
12155

Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition.

We identified a synthetic lethality between PLK1 silencing and the expression of an oncogenic Epidermal Growth Factor Receptor, EGFRvIII. PLK1 promoted homologous recombination (HR), mitigating EGFRvIII induced oncogenic stress resulting from DNA damage accumulation. Accordingly, PLK1 inhibition enhanced the cytotoxic effects of the DNA damaging agent, temozolomide (TMZ). This effect was significantly more pronounced in an Ink4a/Arf(-/-) EGFRvIII glioblastoma model relative to an Ink4a/Arf(-/-) PDGF-β model. The tumoricidal and TMZ-sensitizing effects of BI2536 were uniformly observed across Ink4a/Arf(-/-) EGFRvIII glioblastoma clones that acquired independent resistance mechanisms to EGFR inhibitors, suggesting these resistant clones retain oncogenic stress that required PLK1 compensation. Although BI2536 significantly augmented the anti-neoplastic effect of EGFR inhibitors in the Ink4a/Arf(-/-) EGFRvIII model, durable response was not achieved until TMZ was added. Our results suggest that optimal therapeutic effect against glioblastomas requires a "multi-orthogonal" combination tailored to the molecular physiology associated with the target cancer genome.

Authors
Shen, Y; Li, J; Nitta, M; Futalan, D; Steed, T; Treiber, JM; Taich, Z; Stevens, D; Wykosky, J; Chen, HZ; Carter, BS; Becher, OJ; Kennedy, R; Esashi, F; Sarkaria, JN; Furnari, FB; Cavenee, WK; Desai, A; Chen, CC
MLA Citation
Shen, Y, Li, J, Nitta, M, Futalan, D, Steed, T, Treiber, JM, Taich, Z, Stevens, D, Wykosky, J, Chen, HZ, Carter, BS, Becher, OJ, Kennedy, R, Esashi, F, Sarkaria, JN, Furnari, FB, Cavenee, WK, Desai, A, and Chen, CC. "Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition." Oncotarget 6.14 (May 2015): 11751-11767.
PMID
26059434
Source
epmc
Published In
Oncotarget
Volume
6
Issue
14
Publish Date
2015
Start Page
11751
End Page
11767

A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent.

Diffuse intrinsic pontine gliomas (DIPGs) represent a particularly lethal type of pediatric brain cancer with no effective therapeutic options. Our laboratory has previously reported the development of genetically engineered DIPG mouse models using the RCAS/tv-a system, including a model driven by PDGF-B, H3.3K27M, and p53 loss. These models can serve as a platform in which to test novel therapeutics prior to the initiation of human clinical trials. In this study, an in vitro high-throughput drug screen as part of the DIPG preclinical consortium using cell-lines derived from our DIPG models identified BMS-754807 as a drug of interest in DIPG. BMS-754807 is a potent and reversible small molecule multi-kinase inhibitor with many targets including IGF-1R, IR, MET, TRKA, TRKB, AURKA, AURKB. In vitro evaluation showed significant cytotoxic effects with an IC50 of 0.13 μM, significant inhibition of proliferation at a concentration of 1.5 μM, as well as inhibition of AKT activation. Interestingly, IGF-1R signaling was absent in serum-free cultures from the PDGF-B; H3.3K27M; p53 deficient model suggesting that the antitumor activity of BMS-754807 in this model is independent of IGF-1R. In vivo, systemic administration of BMS-754807 to DIPG-bearing mice did not prolong survival. Pharmacokinetic analysis demonstrated that tumor tissue drug concentrations of BMS-754807 were well below the identified IC50, suggesting that inadequate drug delivery may limit in vivo efficacy. In summary, an unbiased in vitro drug screen identified BMS-754807 as a potential therapeutic agent in DIPG, but BMS-754807 treatment in vivo by systemic delivery did not significantly prolong survival of DIPG-bearing mice.

Authors
Halvorson, KG; Barton, KL; Schroeder, K; Misuraca, KL; Hoeman, C; Chung, A; Crabtree, DM; Cordero, FJ; Singh, R; Spasojevic, I; Berlow, N; Pal, R; Becher, OJ
MLA Citation
Halvorson, KG, Barton, KL, Schroeder, K, Misuraca, KL, Hoeman, C, Chung, A, Crabtree, DM, Cordero, FJ, Singh, R, Spasojevic, I, Berlow, N, Pal, R, and Becher, OJ. "A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent." PloS one 10.3 (January 2015): e0118926-.
Website
http://hdl.handle.net/10161/12567
PMID
25748921
Source
epmc
Published In
PloS one
Volume
10
Issue
3
Publish Date
2015
Start Page
e0118926
DOI
10.1371/journal.pone.0118926

Pre-Clinical Models of Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine glioma (DIPG) is a rare and incurable brain tumor that arises in the brainstem of children predominantly between the ages of 6 and 8. Its intricate morphology and involvement of normal pons tissue precludes surgical resection, and the standard of care today remains fractionated radiation alone. In the past 30 years, there have been no significant advances made in the treatment of DIPG. This is largely because we lack good models of DIPG and therefore have little biological basis for treatment. In recent years, however, due to increased biopsy and acquisition of autopsy specimens, research is beginning to unravel the genetic and epigenetic drivers of DIPG. Insight gleaned from these studies has led to improvements in approaches to both model these tumors in the lab and to potentially treat them in the clinic. This review will detail the initial strides toward modeling DIPG in animals, which included allograft and xenograft rodent models using non-DIPG glioma cells. Important advances in the field came with the development of in vitro cell and in vivo xenograft models derived directly from autopsy material of DIPG patients or from human embryonic stem cells. Finally, we will summarize the progress made in the development of genetically engineered mouse models of DIPG. Cooperation of studies incorporating all of these modeling systems to both investigate the unique mechanisms of gliomagenesis in the brainstem and to test potential novel therapeutic agents in a preclinical setting will result in improvement in treatments for DIPG patients.

Authors
Misuraca, KL; Cordero, FJ; Becher, OJ
MLA Citation
Misuraca, KL, Cordero, FJ, and Becher, OJ. "Pre-Clinical Models of Diffuse Intrinsic Pontine Glioma." Frontiers in oncology 5 (January 2015): 172-. (Review)
Website
http://hdl.handle.net/10161/12566
PMID
26258075
Source
epmc
Published In
Frontiers in Oncology
Volume
5
Publish Date
2015
Start Page
172
DOI
10.3389/fonc.2015.00172

Cancer. For pediatric glioma, leave no histone unturned.

Authors
Becher, OJ; Wechsler-Reya, RJ
MLA Citation
Becher, OJ, and Wechsler-Reya, RJ. "Cancer. For pediatric glioma, leave no histone unturned." Science (New York, N.Y.) 346.6216 (December 2014): 1458-1459.
PMID
25525232
Source
epmc
Published In
Science
Volume
346
Issue
6216
Publish Date
2014
Start Page
1458
End Page
1459
DOI
10.1126/science.aaa3814

SC-37 * THE ROLE OF NG2 EXPRESSING PROGENITOR CELLS IN DIFFUSE INTRINSIC PONTINE GLIOMA

Authors
Yadavilli, S; Becher, OJ; Kambhampati, M; Packer, RJ; Nazarian, J
MLA Citation
Yadavilli, S, Becher, OJ, Kambhampati, M, Packer, RJ, and Nazarian, J. "SC-37 * THE ROLE OF NG2 EXPRESSING PROGENITOR CELLS IN DIFFUSE INTRINSIC PONTINE GLIOMA." Neuro-Oncology 16.suppl 5 (November 1, 2014): v205-v205.
Source
crossref
Published In
Neuro-Oncology
Volume
16
Issue
suppl 5
Publish Date
2014
Start Page
v205
End Page
v205
DOI
10.1093/neuonc/nou275.36

Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma.

High-grade Brainstem Glioma (BSG), also known as Diffuse Intrinsic Pontine Glioma (DIPG), is an incurable pediatric brain cancer. Increasing evidence supports the existence of regional differences in gliomagenesis such that BSG is considered a distinct disease from glioma of the cerebral cortex (CG). In an effort to elucidate unique characteristics of BSG, we conducted expression analysis of mouse PDGF-B-driven BSG and CG initiated in Nestin progenitor cells and identified a short list of expression changes specific to the brainstem gliomagenesis process, including abnormal upregulation of paired box 3 (Pax3). In the neonatal mouse brain, Pax3 expression marks a subset of brainstem progenitor cells, while it is absent from the cerebral cortex, mirroring its regional expression in glioma. Ectopic expression of Pax3 in normal brainstem progenitors in vitro shows that Pax3 inhibits apoptosis. Pax3-induced inhibition of apoptosis is p53-dependent, however, and in the absence of p53, Pax3 promotes proliferation of brainstem progenitors. In vivo, Pax3 enhances PDGF-B-driven gliomagenesis by shortening tumor latency and increasing tumor penetrance and grade, in a region-specific manner, while loss of Pax3 function extends survival of PDGF-B-driven;p53-deficient BSG-bearing mice by 33%. Importantly, Pax3 is regionally expressed in human glioma as well, with high PAX3 mRNA characterizing 40% of human BSG, revealing a subset of tumors that significantly associates with PDGFRA alterations, amplifications of cell cycle regulatory genes, and is exclusive of ACVR1 mutations. Collectively, these data suggest that regional Pax3 expression not only marks a novel subset of BSG but also contributes to PDGF-B-induced brainstem gliomagenesis.

Authors
Misuraca, KL; Barton, KL; Chung, A; Diaz, AK; Conway, SJ; Corcoran, DL; Baker, SJ; Becher, OJ
MLA Citation
Misuraca, KL, Barton, KL, Chung, A, Diaz, AK, Conway, SJ, Corcoran, DL, Baker, SJ, and Becher, OJ. "Pax3 expression enhances PDGF-B-induced brainstem gliomagenesis and characterizes a subset of brainstem glioma." Acta neuropathologica communications 2 (October 21, 2014): 134-.
Website
http://hdl.handle.net/10161/12565
PMID
25330836
Source
epmc
Published In
Acta Neuropathologica Communications
Volume
2
Publish Date
2014
Start Page
134
DOI
10.1186/s40478-014-0134-6

Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications.

Diffuse intrinsic pontine glioma (DIPG) is the main cause of brain tumour-related death in children. In the majority of cases diagnosis is based on clinical and MRI findings, resulting in the scarcity of pre-treatment specimens available to study. Our group has developed an autopsy-based protocol to investigate the histologic and biologic spectrum of DIPG. This has also allowed us to investigate the terminal pattern of disease and gain a better understanding of what challenges we are facing in treating DIPG. Here, we review 72 DIPG cases with well documented clinical history and molecular data and describe the pathological features of this disease in relation to clinical and genetic features. Fifty-three of the samples were autopsy material (7 pre-treatment) and 19 were pre-treatment biopsy/surgical specimens. Upon histological review, 62 patients had high-grade astrocytomas (18 WHO grade III and 44 WHO grade IV patients), 8 had WHO grade II astrocytomas, and 2 had features of primitive neuroectodermal tumour (PNET). K27M-H3 mutations were exclusively found in tumours with WHO grade II-IV astrocytoma histology. K27M-H3.1 and ACVR1 mutations as well as ALT phenotype were only found in WHO grade III-IV astrocytomas, while PIK3CA mutations and PDGFRA gains/amplifications were found in WHO grade II-IV astrocytomas. Approximately 1/3 of DIPG patients had leptomeningeal spread of their tumour. Further, diffuse invasion of the brainstem, spinal cord and thalamus was common with some cases showing spread as distant as the frontal lobes. These findings suggest that focal radiation may be inadequate for some of these patients. Importantly, we show that clinically classic DIPGs represent a diverse histologic spectrum, including multiple cases which would fit WHO criteria of grade II astrocytoma which nevertheless behave clinically as high-grade astrocytomas and harbour the histone K27M-H3.3 mutation. This suggests that the current WHO astrocytoma grading scheme may not appropriately predict outcome for paediatric brainstem gliomas.

Authors
Buczkowicz, P; Bartels, U; Bouffet, E; Becher, O; Hawkins, C
MLA Citation
Buczkowicz, P, Bartels, U, Bouffet, E, Becher, O, and Hawkins, C. "Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications." Acta neuropathologica 128.4 (October 2014): 573-581.
PMID
25047029
Source
epmc
Published In
Acta Neuropathologica
Volume
128
Issue
4
Publish Date
2014
Start Page
573
End Page
581
DOI
10.1007/s00401-014-1319-6

Sox2, a marker for stem-like tumor cells in skin squamous cell carcinoma and hedgehog subgroup medulloblastoma.

Heterogeneity within tumors is becoming increasingly recognized as an important cause of treatment failure in cancer. Two recent studies use fate-mapping and limiting dilution transplantation assays to identify SRY (sex determining region Y)-box 2 (Sox2) as cancer stem-cell marker and driver of cancer stemness.

Authors
Becher, OJ; Holland, EC
MLA Citation
Becher, OJ, and Holland, EC. "Sox2, a marker for stem-like tumor cells in skin squamous cell carcinoma and hedgehog subgroup medulloblastoma." The EMBO journal 33.18 (September 2014): 1984-1986.
PMID
25061226
Source
epmc
Published In
EMBO Journal
Volume
33
Issue
18
Publish Date
2014
Start Page
1984
End Page
1986
DOI
10.15252/embj.201489479

Abcg2 and mdr promote brainstem gliomagenesis and limit the efficacy of dasatinib in a diffuse intrinsic pontine glioma (dipg) mouse model.

DIPG is an incurable tumor that arises in the brainstem of children. Our laboratory generates murine DIPGs by expressing PDGF-B and deleting p53 in nestin progenitors of the neonatal brainstem using the RCAS/tv-a system. Dasatinib, an inhibitor of PDGFR-A and SRC activation, has been evaluated in clinical trials for children with DIPG but with disappointing results. As dasatinib is a substrate of the ABC transporters ABCG2 and MDR, we hypothesized that ABCG2 and MDR may limit the efficacy of dasatinib in DIPG.

Authors
Becher, OJ; Mittapali, R; Chung, AH; Crabtree, D; Elmquist, W
MLA Citation
Becher, OJ, Mittapali, R, Chung, AH, Crabtree, D, and Elmquist, W. "Abcg2 and mdr promote brainstem gliomagenesis and limit the efficacy of dasatinib in a diffuse intrinsic pontine glioma (dipg) mouse model." Neuro Oncol 16 Suppl 3 (July 2014): iii25-.
PMID
25165258
Source
pubmed
Published In
Neuro-Oncology
Volume
16 Suppl 3
Publish Date
2014
Start Page
iii25
DOI
10.1093/neuonc/nou208.8

ABCG2 AND ABCB1 PROMOTE BRAINSTEM GLIOMAGENESIS AND LIMIT THE EFFICACY OF DASATINIB IN A DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) MOUSE MODEL

Authors
Chung, AH; Mittapalli, RK; Elmquist, WF; Becher, OJ
MLA Citation
Chung, AH, Mittapalli, RK, Elmquist, WF, and Becher, OJ. "ABCG2 AND ABCB1 PROMOTE BRAINSTEM GLIOMAGENESIS AND LIMIT THE EFFICACY OF DASATINIB IN A DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) MOUSE MODEL." June 2014.
Source
wos-lite
Published In
Neuro-Oncology
Volume
16
Publish Date
2014
Start Page
46
End Page
47

Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

Authors
Buczkowicz, P; Hoeman, C; Rakopoulos, P; Pajovic, S; Letourneau, L; Dzamba, M; Morrison, A; Lewis, P; Bouffet, E; Bartels, U; Zuccaro, J; Agnihotri, S; Ryall, S; Barszczyk, M; Chornenkyy, Y; Bourgey, M; Bourque, G; Montpetit, A; Cordero, F; Castelo-Branco, P; Mangerel, J; Tabori, U; Ho, KC; Huang, A; Taylor, KR; Mackay, A; Bendel, AE; Nazarian, J; Fangusaro, JR; Karajannis, MA; Zagzag, D; Foreman, NK; Donson, A; Hegert, JV; Smith, A; Chan, J; Lafay-Cousin, L; Dunn, S; Hukin, J; Dunham, C et al.
MLA Citation
Buczkowicz, P, Hoeman, C, Rakopoulos, P, Pajovic, S, Letourneau, L, Dzamba, M, Morrison, A, Lewis, P, Bouffet, E, Bartels, U, Zuccaro, J, Agnihotri, S, Ryall, S, Barszczyk, M, Chornenkyy, Y, Bourgey, M, Bourque, G, Montpetit, A, Cordero, F, Castelo-Branco, P, Mangerel, J, Tabori, U, Ho, KC, Huang, A, Taylor, KR, Mackay, A, Bendel, AE, Nazarian, J, Fangusaro, JR, Karajannis, MA, Zagzag, D, Foreman, NK, Donson, A, Hegert, JV, Smith, A, Chan, J, Lafay-Cousin, L, Dunn, S, Hukin, J, and Dunham, C et al. "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations." Nature genetics 46.5 (May 2014): 451-456.
Website
http://hdl.handle.net/10161/12568
PMID
24705254
Source
epmc
Published In
Nature Genetics
Volume
46
Issue
5
Publish Date
2014
Start Page
451
End Page
456
DOI
10.1038/ng.2936

Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge.

We have extended our understanding of the molecular biology that underlies adult glioblastoma over many years. By contrast, high-grade gliomas in children and adolescents have remained a relatively under-investigated disease. The latest large-scale genomic and epigenomic profiling studies have yielded an unprecedented abundance of novel data and provided deeper insights into gliomagenesis across all age groups, which has highlighted key distinctions but also some commonalities. As we are on the verge of dissecting glioblastomas into meaningful biological subgroups, this Review summarizes the hallmark genetic alterations that are associated with distinct epigenetic features and patient characteristics in both paediatric and adult disease, and examines the complex interplay between the glioblastoma genome and epigenome.

Authors
Sturm, D; Bender, S; Jones, DT; Lichter, P; Grill, J; Becher, O; Hawkins, C; Majewski, J; Jones, C; Costello, JF; Iavarone, A; Aldape, K; Brennan, CW; Jabado, N; Pfister, SM
MLA Citation
Sturm, D, Bender, S, Jones, DT, Lichter, P, Grill, J, Becher, O, Hawkins, C, Majewski, J, Jones, C, Costello, JF, Iavarone, A, Aldape, K, Brennan, CW, Jabado, N, and Pfister, SM. "Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge." Nature reviews. Cancer 14.2 (February 2014): 92-107. (Review)
PMID
24457416
Source
epmc
Published In
Nature Reviews Cancer
Volume
14
Issue
2
Publish Date
2014
Start Page
92
End Page
107
DOI
10.1038/nrc3655

Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer. © 2014 Nature America, Inc. All rights reserved.

Authors
Buczkowicz, P; Hoeman, C; Rakopoulos, P; Pajovic, S; Letourneau, L; Dzamba, M; Morrison, A; Lewis, P; Bouffet, E; Bartels, U; Zuccaro, J; Agnihotri, S; Ryall, S; Barszczyk, M; Chornenkyy, Y; Bourgey, M; Bourque, G; Montpetit, A; Cordero, F; Castelo-Branco, P; Mangerel, J; Tabori, U; Ho, KC; Huang, A; Taylor, KR; Mackay, A; Bendel, AE; Nazarian, J; Fangusaro, JR; Karajannis, MA; Zagzag, D; Foreman, NK; Donson, A; Hegert, JV; Smith, A; Chan, J; Lafay-Cousin, L; Dunn, S; Hukin, J; Dunham, C et al.
MLA Citation
Buczkowicz, P, Hoeman, C, Rakopoulos, P, Pajovic, S, Letourneau, L, Dzamba, M, Morrison, A, Lewis, P, Bouffet, E, Bartels, U, Zuccaro, J, Agnihotri, S, Ryall, S, Barszczyk, M, Chornenkyy, Y, Bourgey, M, Bourque, G, Montpetit, A, Cordero, F, Castelo-Branco, P, Mangerel, J, Tabori, U, Ho, KC, Huang, A, Taylor, KR, Mackay, A, Bendel, AE, Nazarian, J, Fangusaro, JR, Karajannis, MA, Zagzag, D, Foreman, NK, Donson, A, Hegert, JV, Smith, A, Chan, J, Lafay-Cousin, L, Dunn, S, Hukin, J, and Dunham, C et al. "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations." Nature Genetics 46.5 (January 1, 2014): 451-456.
Source
scopus
Published In
Nature Genetics
Volume
46
Issue
5
Publish Date
2014
Start Page
451
End Page
456
DOI
10.1038/ng.2936

Children are not just little adults: recent advances in understanding of diffuse intrinsic pontine glioma biology.

Diffuse intrinsic pontine glioma (DIPG) is a high-grade glioma that originates in the pons and is seen exclusively in children. Despite numerous efforts to improve treatment, DIPG remains incurable with 90% of children dying within 2 y of diagnosis, making it one of the leading causes of death in children with brain tumors. With the advent of new genomic tools, the genetic landscape of DIPG is slowly being unraveled. The most common genetic alterations include a K27M mutation in H3.3 or H3.1, which are found in up to 78% of DIPGs, whereas p53 mutations are found in up to 77%. Other recently discovered alterations include amplification of components of the receptor tyrosine kinase/Ras/phosphatidylinositol 3-kinase signaling pathway, particularly platelet-derived growth factor receptor A. Recapitulating such alterations, genetically engineered DIPG preclinical models have been developed, and DIPG xenograft models have also been established. Both models have strengths and weaknesses but can help with the prioritization of novel agents for clinical trials for children with DIPG. As we move forward, it is important that we continue to study the complex and unique biology of DIPG and develop improved preclinical models to increase our understanding of DIPG pathogenesis, allowing translation into successful therapies in the not too distant future.

Authors
Schroeder, KM; Hoeman, CM; Becher, OJ
MLA Citation
Schroeder, KM, Hoeman, CM, and Becher, OJ. "Children are not just little adults: recent advances in understanding of diffuse intrinsic pontine glioma biology." Pediatr Res 75.1-2 (January 2014): 205-209. (Review)
PMID
24192697
Source
pubmed
Published In
Pediatric Research
Volume
75
Issue
1-2
Publish Date
2014
Start Page
205
End Page
209
DOI
10.1038/pr.2013.194

Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma.

Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B). We report that human diffuse intrinsic pontine gliomas (DIPGs) containing the K27M mutation display significantly lower overall amounts of H3 with trimethylated lysine 27 (H3K27me3) and that histone H3K27M transgenes are sufficient to reduce the amounts of H3K27me3 in vitro and in vivo. We find that H3K27M inhibits the enzymatic activity of the Polycomb repressive complex 2 through interaction with the EZH2 subunit. In addition, transgenes containing lysine-to-methionine substitutions at other known methylated lysines (H3K9 and H3K36) are sufficient to cause specific reduction in methylation through inhibition of SET-domain enzymes. We propose that K-to-M substitutions may represent a mechanism to alter epigenetic states in a variety of pathologies.

Authors
Lewis, PW; Müller, MM; Koletsky, MS; Cordero, F; Lin, S; Banaszynski, LA; Garcia, BA; Muir, TW; Becher, OJ; Allis, CD
MLA Citation
Lewis, PW, Müller, MM, Koletsky, MS, Cordero, F, Lin, S, Banaszynski, LA, Garcia, BA, Muir, TW, Becher, OJ, and Allis, CD. "Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma." Science 340.6134 (May 17, 2013): 857-861.
PMID
23539183
Source
pubmed
Published In
Science
Volume
340
Issue
6134
Publish Date
2013
Start Page
857
End Page
861
DOI
10.1126/science.1232245

Abstract 5004: NG2 upregulation and its defective asymmetric distribution in pediatric brainstem glioma and diffuse intrinsic pontine glioma.

Authors
Yadavilli, S; Kambhampati, M; Becher, OJ; MacDonald, T; Bellamkonda, R; Paker, RJ; Nazarian, J
MLA Citation
Yadavilli, S, Kambhampati, M, Becher, OJ, MacDonald, T, Bellamkonda, R, Paker, RJ, and Nazarian, J. "Abstract 5004: NG2 upregulation and its defective asymmetric distribution in pediatric brainstem glioma and diffuse intrinsic pontine glioma." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
5004
End Page
5004
DOI
10.1158/1538-7445.AM2013-5004

ABC TRANSPORTERS, ABCG2 AND MDR, LIMIT THE EFFICACY OF DASATINIB IN A DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) MOUSE MODEL.

Authors
Chung, AH; Crabtree, D; Schroeder, K; Becher, OJ
MLA Citation
Chung, AH, Crabtree, D, Schroeder, K, and Becher, OJ. "ABC TRANSPORTERS, ABCG2 AND MDR, LIMIT THE EFFICACY OF DASATINIB IN A DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG) MOUSE MODEL." April 2013.
Source
wos-lite
Published In
Neuro-Oncology
Volume
15
Publish Date
2013
Start Page
29
End Page
30

Aurora kinase B is a potential therapeutic target in pediatric diffuse intrinsic pontine glioma

Pediatric high-grade astrocytomas (HGAs) account for 15-20% of all pediatric central nervous system tumors. These neoplasms predominantly involve the supratentorial hemispheres or the pons - diffuse intrinsic pontine gliomas (DIPG). Assumptions that pediatric HGAs are biologically similar to adult HGAs have recently been challenged, and the development of effective therapeutic modalities for DIPG and supratentorial HGA hinges on a better understanding of their biological properties. Here, 20 pediatric HGAs (9 DIPGs and 11 supratentorial HGAs) were subject to gene expression profiling following approval by the research ethics board at our institution. Many of these tumors showed expression signatures composed of genes that promote G1/S and G2/M cell cycle progression. In particular, Aurora kinase B (AURKB) was consistently and highly overexpressed in 6/9 DIPGs and 8/11 HGAs. Array data were validated using quantitative real-time PCR and immunohistochemistry, as well as cross-validation of our data set with previously published series. Inhibition of Aurora B activity in DIPG and in pediatric HGA cell lines resulted in growth arrest accompanied by morphological changes, cell cycle aberrations, nuclear fractionation and polyploidy as well as a reduction in colony formation. Our data highlight Aurora B as a potential therapeutic target in DIPG. © 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.

Authors
Buczkowicz, P; Zarghooni, M; Bartels, U; Morrison, A; Misuraca, KL; Chan, T; Bouffet, E; Huang, A; Becher, O; Hawkins, C
MLA Citation
Buczkowicz, P, Zarghooni, M, Bartels, U, Morrison, A, Misuraca, KL, Chan, T, Bouffet, E, Huang, A, Becher, O, and Hawkins, C. "Aurora kinase B is a potential therapeutic target in pediatric diffuse intrinsic pontine glioma." Brain Pathology 23.3 (2013): 244-253.
PMID
22971244
Source
scival
Published In
Brain Pathology
Volume
23
Issue
3
Publish Date
2013
Start Page
244
End Page
253
DOI
10.1111/j.1750-3639.2012.00633.x

Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma

Sequencing of pediatric gliomas has identified missense mutations Lys27Met (K27M) and Gly34Arg/Val (G34R/V) in genes encoding histone H3.3 (H3F3A) and H3.1 (HIST3H1B). We report that human diffuse intrinsic pontine gliomas (DIPGs) containing the K27M mutation display significantly lower overall amounts of H3 with trimethylated lysine 27 (H3K27me3) and that histone H3K27M transgenes are sufficient to reduce the amounts of H3K27me3 in vitro and in vivo. We find that H3K27M inhibits the enzymatic activity of the Polycomb repressive complex 2 through interaction with the EZH2 subunit. In addition, transgenes containing lysine-to-methionine substitutions at other known methylated lysines (H3K9 and H3K36) are sufficient to cause specific reduction in methylation through inhibition of SET-domain enzymes. We propose that K-to-M substitutions may represent a mechanism to alter epigenetic states in a variety of pathologies.

Authors
Lewis, PW; Müller, MM; Koletsky, MS; Cordero, F; Lin, S; Banaszynski, LA; Garcia, BA; Muir, TW; Becher, OJ; Allis, CD
MLA Citation
Lewis, PW, Müller, MM, Koletsky, MS, Cordero, F, Lin, S, Banaszynski, LA, Garcia, BA, Muir, TW, Becher, OJ, and Allis, CD. "Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma." Science 340.6134 (2013): 857-861.
Source
scival
Published In
Science
Volume
340
Issue
6134
Publish Date
2013
Start Page
857
End Page
861
DOI
10.1126/science.1232245

PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma.

Diffuse intrinsic pontine glioma (DIPG) is an incurable tumor that arises in the brainstem of children. To date there is not a single approved drug to effectively treat these tumors and thus novel therapies are desperately needed. Recent studies suggest that a significant fraction of these tumors contain alterations in cell cycle regulatory genes including amplification of the D-type cyclins and CDK4/6, and less commonly, loss of Ink4a-ARF leading to aberrant cell proliferation. In this study, we evaluated the therapeutic approach of targeting the cyclin-CDK-Retinoblastoma (Rb) pathway in a genetically engineered PDGF-B-driven brainstem glioma (BSG) mouse model. We found that PD-0332991 (PD), a CDK4/6 inhibitor, induces cell-cycle arrest in our PDGF-B; Ink4a-ARF deficient model both in vitro and in vivo. By contrast, the PDGF-B; p53 deficient model was mostly resistant to treatment with PD. We noted that a 7-day treatment course with PD significantly prolonged survival by 12% in the PDGF-B; Ink4a-ARF deficient BSG model. Furthermore, a single dose of 10 Gy radiation therapy (RT) followed by 7 days of treatment with PD increased the survival by 19% in comparison to RT alone. These findings provide the rationale for evaluating PD in children with Ink4a-ARF deficient gliomas.

Authors
Barton, KL; Misuraca, K; Cordero, F; Dobrikova, E; Min, HD; Gromeier, M; Kirsch, DG; Becher, OJ
MLA Citation
Barton, KL, Misuraca, K, Cordero, F, Dobrikova, E, Min, HD, Gromeier, M, Kirsch, DG, and Becher, OJ. "PD-0332991, a CDK4/6 inhibitor, significantly prolongs survival in a genetically engineered mouse model of brainstem glioma. (Published online)" PLoS One 8.10 (2013): e77639-.
PMID
24098593
Source
pubmed
Published In
PloS one
Volume
8
Issue
10
Publish Date
2013
Start Page
e77639
DOI
10.1371/journal.pone.0077639

Reirradiation for recurrent medulloblastoma.

BACKGROUND: Previously irradiated recurrent medulloblastoma (MB) is a highly lethal disease. Reirradiation is often not considered secondary to its potential toxicity and uncertain efficacy. Analysis of retreatment could help identify the feasibility and role of reirradiation for recurrent MB. METHODS: Thirteen patients who underwent at least 1 course of reirradiation at the authors' institution as a component of management after recurrence were identified, and their medical records were analyzed. RESULTS: At first diagnosis, all patients underwent surgical resection and radiation, with 69% of patients receiving chemotherapy. Median time to initial failure was 50 months (range, 14-103 months). Reirradiation subsite breakdown was as follows: posterior fossa, 46%; supratentorial/whole brain, 31%; spine, 23%; craniospinal, 8%. Median cumulative dose was 84 grays (range, 65-98.4 grays). Of 11 patients completing a full course of reirradiation, there were 6 failures, with 3 in the reirradiation field. Kaplan-Meier estimates of progression-free and overall survival since time of first recurrence were 48% and 65%, respectively at 5 years. Of patients without gross disease at reirradiation, 83% were without evidence of disease at last follow-up. With a median follow-up of 30 months, reirradiation was well tolerated, with only 1 case of asymptomatic, in-field radiation necrosis. CONCLUSIONS: The results in this series are promising, but must be interpreted with caution given the limitations. Reirradiation provided most benefit to patients with no evidence of disease after surgical re-resection, and least to patients with gross disease. Important considerations for reirradiation toxicity development include duration between radiation courses and patient age. Further study of reirradiation as part of trimodality therapy is warranted.

Authors
Bakst, RL; Dunkel, IJ; Gilheeney, S; Khakoo, Y; Becher, O; Souweidane, MM; Wolden, SL
MLA Citation
Bakst, RL, Dunkel, IJ, Gilheeney, S, Khakoo, Y, Becher, O, Souweidane, MM, and Wolden, SL. "Reirradiation for recurrent medulloblastoma." Cancer 117.21 (November 1, 2011): 4977-4982.
PMID
21495027
Source
pubmed
Published In
Cancer
Volume
117
Issue
21
Publish Date
2011
Start Page
4977
End Page
4982
DOI
10.1002/cncr.26148

Disease control and ototoxicity using intensity-modulated radiation therapy tumor-bed boost for medulloblastoma.

PURPOSE: We previously reported excellent local control for treating medulloblastoma with a limited boost to the tumor bed. In order to decrease ototoxicity, we subsequently implemented a tumor-bed boost using intensity-modulated radiation therapy (IMRT), the clinical results of which we report here. PATIENTS AND METHODS: A total of 33 patients with newly diagnosed medulloblastoma, 25 with standard risk, and 8 with high risk, were treated on an IMRT tumor-bed boost following craniospinal irradiation (CSI). Six standard-risk patients were treated with an institutional protocol with 18 Gy CSI in conjunction with intrathecal iodine-131-labeled monoclonal antibody. The majority of patients received concurrent vincristine and standard adjuvant chemotherapy. Pure-tone audiograms were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. RESULTS: Median age was 9 years old (range, 4-46 years old). Median follow-up was 63 months. Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) rates for standard-risk patients who received 23.4 or 36 Gy CSI (not including those who received 18 Gy CSI with radioimmunotherapy) were 81.4% and 88.4%, respectively, at 5 years; 5-year PFS and OS rates for high-risk patients were both 87.5%. There were no isolated posterior fossa failures outside of the boost volume. Posttreatment audiograms were available for 31 patients, of whom 6%, at a median follow-up of 19 months, had developed Grade 3 hearing loss. CONCLUSION: An IMRT tumor-bed boost results in excellent local control while delivering a low mean dose to the cochlea, resulting in a low rate of ototoxicity.

Authors
Polkinghorn, WR; Dunkel, IJ; Souweidane, MM; Khakoo, Y; Lyden, DC; Gilheeney, SW; Becher, OJ; Budnick, AS; Wolden, SL
MLA Citation
Polkinghorn, WR, Dunkel, IJ, Souweidane, MM, Khakoo, Y, Lyden, DC, Gilheeney, SW, Becher, OJ, Budnick, AS, and Wolden, SL. "Disease control and ototoxicity using intensity-modulated radiation therapy tumor-bed boost for medulloblastoma." Int J Radiat Oncol Biol Phys 81.3 (November 1, 2011): e15-e20.
PMID
21481547
Source
pubmed
Published In
International Journal of Radiation: Oncology - Biology - Physics
Volume
81
Issue
3
Publish Date
2011
Start Page
e15
End Page
e20
DOI
10.1016/j.ijrobp.2010.11.081

Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-deficient PDGF-driven murine glioblastoma.

BACKGROUND: Platelet derived growth factor receptor (PDGFR) activity is deregulated in human GBM due to amplification and rearrangement of the PDGFR-alpha gene locus or overexpression of the PDGF ligand, resulting in the activation of downstream kinases such as phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR). Aberrant PDGFR signaling is observed in approximately 25-30% of human GBMs, which are frequently molecularly classified as the proneural subclass. It would be valuable to understand how PDGFR driven GBMs respond to Akt and mTOR inhibition. METHODOLOGY/PRINCIPAL FINDINGS: Using genetically engineered PTEN-intact and PTEN-deficient PDGF-driven mouse models of GBM that closely mimic the histology and genetics of the human PDGF subgroup, we investigated the effect of inhibiting Akt and mTOR alone or in combination in vitro and in vivo. We used perifosine and CCI-779 to inhibit Akt and mTOR, respectively. Here, we show in vitro data demonstrating that the most effective inhibition of Akt and mTOR activity in both PTEN-intact and PTEN-null primary glioma cell cultures is obtained when using both inhibitors in combination. We next investigated if the effects we observed in culture could be duplicated in vivo by treating mice with gliomas for 5 days. The in vivo treatments with the combination of CCI-779 and perifosine resulted in decreased Akt and mTOR signaling, which correlated to decreased proliferation and increased cell death independent of PTEN status, as monitored by immunoblot analysis, histology and MRI. CONCLUSIONS/SIGNIFICANCE: These findings underline the importance of simultaneously targeting Akt and mTOR to achieve significant down-regulation of the PI3K pathway and support the rationale for testing the perifosine and CCI-779 combination in the human PDGF-subgroup of GBM.

Authors
Pitter, KL; Galbán, CJ; Galbán, S; Tehrani, OS; Li, F; Charles, N; Bradbury, MS; Becher, OJ; Chenevert, TL; Rehemtulla, A; Ross, BD; Holland, EC; Hambardzumyan, D
MLA Citation
Pitter, KL, Galbán, CJ, Galbán, S, Tehrani, OS, Li, F, Charles, N, Bradbury, MS, Becher, OJ, Chenevert, TL, Rehemtulla, A, Ross, BD, Holland, EC, and Hambardzumyan, D. "Perifosine and CCI 779 co-operate to induce cell death and decrease proliferation in PTEN-intact and PTEN-deficient PDGF-driven murine glioblastoma. (Published online)" PLoS One 6.1 (January 18, 2011): e14545-.
PMID
21267448
Source
pubmed
Published In
PloS one
Volume
6
Issue
1
Publish Date
2011
Start Page
e14545
DOI
10.1371/journal.pone.0014545

Evidence for and against regional differences in neural stem and progenitor cells of the CNS.

Neural stem and progenitor cells (NSCs) give rise to the cellular diversity of the CNS. There is evidence both for and against differences in these cells based on the region of the brain in which they reside. Primary brain tumors mimic many aspects of NSC behavior. Recent data suggest that some of the variability in glioma biology may be, in part, a reflection of regional differences in the NSCs from which they arise. In this issue of Genes & Development, Lee and colleagues (pp. 2317-2329) examine how NF1 regulates NSC proliferation and glial differentiation in the brainstem and cortex of the postnatal mouse brain.

Authors
Becher, OJ; Holland, EC
MLA Citation
Becher, OJ, and Holland, EC. "Evidence for and against regional differences in neural stem and progenitor cells of the CNS." Genes Dev 24.20 (October 15, 2010): 2233-2238.
PMID
20952533
Source
pubmed
Published In
Genes & development
Volume
24
Issue
20
Publish Date
2010
Start Page
2233
End Page
2238
DOI
10.1101/gad.1988010

PHASE I STUDY OF PERIFOSINE (AKT INHIBITOR) FOR RECURRENT PEDIATRIC SOLID TUMORS

Authors
Becher, OJ; Trippett, T; Gilheeney, S; Khakoo, Y; Lyden, D; Haque, S; Petriccione, M; Camelia, S; Lassman, A; Fischer, C; Kolesar, J; Jiang, Z; Modak, S; Holland, E; Dunkel, I
MLA Citation
Becher, OJ, Trippett, T, Gilheeney, S, Khakoo, Y, Lyden, D, Haque, S, Petriccione, M, Camelia, S, Lassman, A, Fischer, C, Kolesar, J, Jiang, Z, Modak, S, Holland, E, and Dunkel, I. "PHASE I STUDY OF PERIFOSINE (AKT INHIBITOR) FOR RECURRENT PEDIATRIC SOLID TUMORS." June 2010.
Source
wos-lite
Published In
Neuro-Oncology
Volume
12
Issue
6
Publish Date
2010
Start Page
II42
End Page
II42

TREATMENT STRATEGIES FOR RECURRENT MEDULLOBLASTOMA - REPORT OF A SINGLE INSTITUTION EXPERIENCE

Authors
Gilheeney, SW; McLaren, S; Dreyfus, H; Becher, OJ; Khakoo, Y; Kramer, K; Lyden, DC; Souweidane, M; Wolden, S; Dunkel, IJ
MLA Citation
Gilheeney, SW, McLaren, S, Dreyfus, H, Becher, OJ, Khakoo, Y, Kramer, K, Lyden, DC, Souweidane, M, Wolden, S, and Dunkel, IJ. "TREATMENT STRATEGIES FOR RECURRENT MEDULLOBLASTOMA - REPORT OF A SINGLE INSTITUTION EXPERIENCE." June 2010.
Source
wos-lite
Published In
Neuro-Oncology
Volume
12
Issue
6
Publish Date
2010
Start Page
II62
End Page
II62

A TRIAL OF INTRA-OMMAYA (IO) RADIOIMMUNOTHERAPY (RIT), REDUCED-DOSE EXTERNAL BEAM CRANIOSPINAL RADIOTHERAPY (RT) WITH INTENSITY-MODULATED RADIOTHERAPY (IMRT) BOOST, AND CHEMOTHERAPY FOR PATIENTS WITH STANDARD-RISK MEDULLOBLASTOMA

Authors
Dunkel, IJ; Wolden, SL; Souweidane, MM; Sklar, CA; Khakoo, Y; Larson, SM; Becher, OJ; Gershon, TR; Gilheeney, SW; Lyden, DC; Hague, S; Lis, E; Rosenblum, MK; Thaler, HT; Kramer, K
MLA Citation
Dunkel, IJ, Wolden, SL, Souweidane, MM, Sklar, CA, Khakoo, Y, Larson, SM, Becher, OJ, Gershon, TR, Gilheeney, SW, Lyden, DC, Hague, S, Lis, E, Rosenblum, MK, Thaler, HT, and Kramer, K. "A TRIAL OF INTRA-OMMAYA (IO) RADIOIMMUNOTHERAPY (RIT), REDUCED-DOSE EXTERNAL BEAM CRANIOSPINAL RADIOTHERAPY (RT) WITH INTENSITY-MODULATED RADIOTHERAPY (IMRT) BOOST, AND CHEMOTHERAPY FOR PATIENTS WITH STANDARD-RISK MEDULLOBLASTOMA." June 2010.
Source
wos-lite
Published In
Neuro-Oncology
Volume
12
Issue
6
Publish Date
2010
Start Page
II60
End Page
II60

Heterozygosity for Pten promotes tumorigenesis in a mouse model of medulloblastoma.

BACKGROUND: Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma. METHODOLOGY/PRINCIPAL FINDINGS: We crossed mice with constitutive activation of Smoothened, SmoA1, with Pten deficient mice. Both constitutive and conditional Pten deficiency doubled the incidence of mice with symptoms of medulloblastoma and resulted in decreased survival. Analysis revealed a clear separation of gene signatures, with up-regulation of genes in the PI-3 kinase signaling pathway, including downstream activation of angiogenesis in SmoA1+/-; Pten +/- medulloblastomas. Western blotting and immunohistochemistry confirmed reduced or absent Pten, Akt activation, and increased angiogenesis in Pten deficient tumors. Down-regulated genes included genes in the sonic hedgehog pathway and tumor suppressor genes. SmoA1+/-; Pten +/+ medulloblastomas appeared classic in histology with increased proliferation and diffuse staining for apoptosis. In contrast, Pten deficient tumors exhibited extensive nodularity with neuronal differentiation separated by focal areas of intense staining for proliferation and virtually absent apoptosis. Examination of human medulloblastomas revealed low to absent PTEN expression in over half of the tumors. Kaplan-Meier analysis confirmed worse overall survival in patients whose tumor exhibited low to absent PTEN expression. CONCLUSIONS/SIGNIFICANCE: This suggests that PTEN expression is a marker of favorable prognosis and mouse models with activation of PI-3 kinase pathways may be important tools for preclinical evaluation of promising agents for the treatment of medulloblastoma.

Authors
Castellino, RC; Barwick, BG; Schniederjan, M; Buss, MC; Becher, O; Hambardzumyan, D; Macdonald, TJ; Brat, DJ; Durden, DL
MLA Citation
Castellino, RC, Barwick, BG, Schniederjan, M, Buss, MC, Becher, O, Hambardzumyan, D, Macdonald, TJ, Brat, DJ, and Durden, DL. "Heterozygosity for Pten promotes tumorigenesis in a mouse model of medulloblastoma. (Published online)" PLoS One 5.5 (May 26, 2010): e10849-.
PMID
20520772
Source
pubmed
Published In
PloS one
Volume
5
Issue
5
Publish Date
2010
Start Page
e10849
DOI
10.1371/journal.pone.0010849

Phase I study of single-agent perifosine for recurrent pediatric solid tumors.

Authors
Becher, OJ; Trippett, TM; Kolesar, J; Gilheeney, S; Jiang, Z; Khakoo, Y; Lyden, D; Sima, C; Holland, EC; Dunkel, IJ
MLA Citation
Becher, OJ, Trippett, TM, Kolesar, J, Gilheeney, S, Jiang, Z, Khakoo, Y, Lyden, D, Sima, C, Holland, EC, and Dunkel, IJ. "Phase I study of single-agent perifosine for recurrent pediatric solid tumors." JOURNAL OF CLINICAL ONCOLOGY 28.15 (May 20, 2010).
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
28
Issue
15
Publish Date
2010

Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma.

Brainstem gliomas (BSG) are a rare group of central nervous system tumors that arise mostly in children and usually portend a particularly poor prognosis. We report the development of a genetically engineered mouse model of BSG using the RCAS/tv-a system and its implementation in preclinical trials. Using immunohistochemistry, we found that platelet-derived growth factor (PDGF) receptor alpha is overexpressed in 67% of pediatric BSGs. Based on this observation, we induced low-grade BSGs by overexpressing PDGF-B in the posterior fossa of neonatal nestin tv-a mice. To generate high-grade BSGs, we overexpressed PDGF-B in combination with Ink4a-ARF loss, given that this locus is commonly lost in high-grade pediatric BSGs. We show that the likely cells of origin for these mouse BSGs exist on the floor of the fourth ventricle and cerebral aqueduct. Irradiation of these high-grade BSGs shows that although single doses of 2, 6, and 10 Gy significantly increased the percent of terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei, only 6 and 10 Gy significantly induce cell cycle arrest. Perifosine, an inhibitor of AKT signaling, significantly induced TUNEL-positive nuclei in this high-grade BSG model, but in combination with 10 Gy, it did not significantly increase the percent of TUNEL-positive nuclei relative to 10 Gy alone at 6, 24, and 72 hours. Survival analysis showed that a single dose of 10 Gy significantly prolonged survival by 27% (P = 0.0002) but perifosine did not (P = 0.92). Perifosine + 10 Gy did not result in a significantly increased survival relative to 10 Gy alone (P = 0.23). This PDGF-induced BSG model can serve as a preclinical tool for the testing of novel agents.

Authors
Becher, OJ; Hambardzumyan, D; Walker, TR; Helmy, K; Nazarian, J; Albrecht, S; Hiner, RL; Gall, S; Huse, JT; Jabado, N; MacDonald, TJ; Holland, EC
MLA Citation
Becher, OJ, Hambardzumyan, D, Walker, TR, Helmy, K, Nazarian, J, Albrecht, S, Hiner, RL, Gall, S, Huse, JT, Jabado, N, MacDonald, TJ, and Holland, EC. "Preclinical evaluation of radiation and perifosine in a genetically and histologically accurate model of brainstem glioma." Cancer Res 70.6 (March 15, 2010): 2548-2557.
PMID
20197468
Source
pubmed
Published In
Cancer Research
Volume
70
Issue
6
Publish Date
2010
Start Page
2548
End Page
2557
DOI
10.1158/0008-5472.CAN-09-2503

Heterozygosity for Pten promotes tumorigenesis in a mouse model of medulloblastoma.

BACKGROUND: Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma. METHODOLOGY/PRINCIPAL FINDINGS: We crossed mice with constitutive activation of Smoothened, SmoA1, with Pten deficient mice. Both constitutive and conditional Pten deficiency doubled the incidence of mice with symptoms of medulloblastoma and resulted in decreased survival. Analysis revealed a clear separation of gene signatures, with up-regulation of genes in the PI-3 kinase signaling pathway, including downstream activation of angiogenesis in SmoA1+/-; Pten +/- medulloblastomas. Western blotting and immunohistochemistry confirmed reduced or absent Pten, Akt activation, and increased angiogenesis in Pten deficient tumors. Down-regulated genes included genes in the sonic hedgehog pathway and tumor suppressor genes. SmoA1+/-; Pten +/+ medulloblastomas appeared classic in histology with increased proliferation and diffuse staining for apoptosis. In contrast, Pten deficient tumors exhibited extensive nodularity with neuronal differentiation separated by focal areas of intense staining for proliferation and virtually absent apoptosis. Examination of human medulloblastomas revealed low to absent PTEN expression in over half of the tumors. Kaplan-Meier analysis confirmed worse overall survival in patients whose tumor exhibited low to absent PTEN expression. CONCLUSIONS/SIGNIFICANCE: This suggests that PTEN expression is a marker of favorable prognosis and mouse models with activation of PI-3 kinase pathways may be important tools for preclinical evaluation of promising agents for the treatment of medulloblastoma.

Authors
Castellino, RC; Barwick, BG; Schniederjan, M; Buss, MC; Becher, O; Hambardzumyan, D; Macdonald, TJ; Brat, DJ; Durden, DL
MLA Citation
Castellino, RC, Barwick, BG, Schniederjan, M, Buss, MC, Becher, O, Hambardzumyan, D, Macdonald, TJ, Brat, DJ, and Durden, DL. "Heterozygosity for Pten promotes tumorigenesis in a mouse model of medulloblastoma." PloS one 5.5 (2010): e10849-.
Source
scival
Published In
PloS one
Volume
5
Issue
5
Publish Date
2010
Start Page
e10849
DOI
10.1371/journal.pone.0010849

Sonic hedgehog pathway activation is induced by acute brain injury and regulated by injury-related inflammation.

The adult mammalian brain responds to injury by activating a program of cell proliferation during which many oligodendrocyte precursors, microglia, and some astrocytes proliferate. Another common response to brain injury is the induction of reactive gliosis, a process whereby dormant astrocytes undergo morphological changes and alter their transcriptional profiles. Although brain injury-induced reactive gliosis is concurrent with the proliferation of surrounding cells, a functional relationship between reactive gliosis and this cell proliferation has not been clearly demonstrated. Here, we show that the mitogen sonic hedgehog (SHH) is produced in reactive astrocytes after injury to the cerebral cortex and participates in regulating the proliferation of Olig2-expressing (Olig2(+)) cells after brain injury. Using a cortical freeze injury to induce reactive gliosis in a Gli-luciferase reporter mouse, we show that the SHH pathway is maximally active 3 d after brain injury and returns to baseline levels by 14 d. SHH expression parallels Gli activation and localizes to glial fibrillary acidic protein-expressing reactive astrocytes. Inhibition of the SHH pathway with cyclopamine blocks the Gli response and significantly reduces both the proliferating and overall number of Olig2(+) cells in the injured cortex. To provide mechanistic insight into SHH pathway activation in astrocytes, we show that proinflammatory stimuli activate SHH-expressing reactive astrocytes, whereas inhibition of inflammation-induced reactive gliosis by macrophage depletion abolishes SHH activation after brain injury and dampens cell proliferation after injury. Our data describes a unique reactive astrocyte-based, SHH-expressing niche formed in response to injury and inflammation that regulates the proliferation of Olig2(+) cells.

Authors
Amankulor, NM; Hambardzumyan, D; Pyonteck, SM; Becher, OJ; Joyce, JA; Holland, EC
MLA Citation
Amankulor, NM, Hambardzumyan, D, Pyonteck, SM, Becher, OJ, Joyce, JA, and Holland, EC. "Sonic hedgehog pathway activation is induced by acute brain injury and regulated by injury-related inflammation." J Neurosci 29.33 (August 19, 2009): 10299-10308.
PMID
19692604
Source
pubmed
Published In
The Journal of neuroscience : the official journal of the Society for Neuroscience
Volume
29
Issue
33
Publish Date
2009
Start Page
10299
End Page
10308
DOI
10.1523/JNEUROSCI.2500-09.2009

Modeling Adult Gliomas Using RCAS/t-va Technology.

Malignant gliomas remain the most devastating childhood and adult tumors of the central nervous system. Although adult and pediatric gliomas are histologically indistinguishable, they differ in location, behavior, and molecular characteristics. This implies that the molecular pathways and pathophysiology of malignant gliomagenesis in these two populations are distinct. Such differences between adult and pediatric gliomas may predict different therapeutic responses. Therefore, accurate genetically engineered models of adult and pediatric gliomas may help understand the biology of these tumors and evaluate therapeutic agents in preclinical studies. It has been proposed that gliomas arise from the subventricular zone in mice during development. Here, we demonstrate that, in adult mice, gliomas may arise not only when injected in the subventricular zone but also when injected in the cortex and cerebellum. Our work demonstrates a versatile and highly reproducible adult mouse model of glioma, which can be easily incorporated into preclinical studies.

Authors
Hambardzumyan, D; Amankulor, NM; Helmy, KY; Becher, OJ; Holland, EC
MLA Citation
Hambardzumyan, D, Amankulor, NM, Helmy, KY, Becher, OJ, and Holland, EC. "Modeling Adult Gliomas Using RCAS/t-va Technology." Transl Oncol 2.2 (May 2009): 89-95.
PMID
19412424
Source
pubmed
Published In
Translational oncology
Volume
2
Issue
2
Publish Date
2009
Start Page
89
End Page
95

Large congenital melanotic nevi in an extremity with neurocutaneous melanocytosis.

A 14-day-old boy presented with a large congenital melanocytic nevus over his left thigh with approximately 17 satellite nevi distributed over the rest of his skin surface. Six weeks later, he developed generalized tonic-clonic seizures and additional satellite nevi became apparent (n > 20). A subsequent brain magnetic resonance imaging demonstrated right temporal T1 hyperintense signal abnormality. At 4 months of age the patient underwent a lumbar puncture that was normal without evidence of melanocytes or tumor. Nevertheless, a few days later he underwent resection of his right medial temporal lesion which demonstrated melanocytosis in the temporal lobe as well as melanocytosis in subependymal areas in other parts of the brain and ventricles, confirming the suspected diagnosis of neurocutaneous melanocytosis. Our case supports previous studies that conclude that the number of satellite nevi is a greater predictor of neurocutaneous melanocytosis than is the location of large congenital melanocytic nevus. In our case, cerebrospinal fluid studies were not reliable even in the face of florid neurocutaneous melanocytosis involving the leptomeninges and ventricles.

Authors
Becher, OJ; Souweidane, M; Lavi, E; Kramer, K; Lis, E; Marghoob, AA; Khakoo, Y
MLA Citation
Becher, OJ, Souweidane, M, Lavi, E, Kramer, K, Lis, E, Marghoob, AA, and Khakoo, Y. "Large congenital melanotic nevi in an extremity with neurocutaneous melanocytosis." Pediatr Dermatol 26.1 (January 2009): 79-82.
PMID
19250413
Source
pubmed
Published In
Pediatric Dermatology
Volume
26
Issue
1
Publish Date
2009
Start Page
79
End Page
82
DOI
10.1111/j.1525-1470.2008.00828.x

IGFBP2 is overexpressed by pediatric malignant astrocytomas and induces the repair enzyme DNA-PK.

To identify targets critical to malignant childhood astrocytoma, we compared the expression of receptor tyrosine kinase- associated genes between low-grade and high-grade pediatric astrocytomas. The highest differentially overexpressed gene in high-grade astrocytoma is insulin-like growth factor- binding protein-2 (P = .0006). Immunohistochemistry confirmed overexpression of insulin-like growth factor-binding protein-2 protein (P = .027). Insulin-like growth factor- binding protein-2 stimulation had no effect on astrocytoma cell growth and migration, and minimally inhibited insulin-like growth factor-1-mediated migration, but not insulin-like growth factor-2-mediated migration. However, insulin-like growth factor-binding protein-2 stimulation significantly upregulated the major DNA repair enzyme gene, DNA-PKcs, and induced DNA-dependent protein kinase catalytic subunit protein expression in a time-dependent and dose-dependent manner, whereas insulin-like growth factor-1 had no effect. DNA-PKcs is also highly overexpressed by high-grade astrocytomas. These findings suggest insulin-like growth factor-binding protein-2 plays a role in astrocytoma progression by promoting DNA-damage repair and therapeutic resistance.

Authors
Becher, OJ; Peterson, KM; Khatua, S; Santi, MR; MacDonald, TJ
MLA Citation
Becher, OJ, Peterson, KM, Khatua, S, Santi, MR, and MacDonald, TJ. "IGFBP2 is overexpressed by pediatric malignant astrocytomas and induces the repair enzyme DNA-PK." J Child Neurol 23.10 (October 2008): 1205-1213.
PMID
18952587
Source
pubmed
Published In
Journal of Child Neurology
Volume
23
Issue
10
Publish Date
2008
Start Page
1205
End Page
1213
DOI
10.1177/0883073808321766

Cancer stem cells and survival pathways.

Gliomas and medulloblastomas are the most frequent malignant brain tumors in adult and children respectively. Although both tumors arise in the CNS, there is a significant difference in their therapeutic response. Medulloblastomas are relatively curable, while glioblastomas are basically incurable. During the last decade several reports have demonstrated the existence of cancer stem cells in brain tumors, their location and their response to treatment. We have recently described the therapeutic response of medulloblastomas to radiation in their native microenvironment, illustrating how p53 and Pi3K signaling pathways lead to the evasion of cell death by the nestin-expressing cells in the perivascular stem cell niche, even while the bulk of tumor succumbs to apoptosis.(1) It remains to be determined whether this mechanism of tumor resistance applies to the more complex stem-cell niche and tumor bulk of gliomas.

Authors
Hambardzumyan, D; Becher, OJ; Holland, EC
MLA Citation
Hambardzumyan, D, Becher, OJ, and Holland, EC. "Cancer stem cells and survival pathways." Cell Cycle 7.10 (May 15, 2008): 1371-1378. (Review)
PMID
18421251
Source
pubmed
Published In
Cell Cycle
Volume
7
Issue
10
Publish Date
2008
Start Page
1371
End Page
1378
DOI
10.4161/cc.7.10.5954

Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas.

Gli signaling is critical for central nervous system development and is implicated in tumorigenesis. To monitor Gli signaling in gliomas in vivo, we created platelet-derived growth factor-induced gliomas in a Gli-luciferase reporter mouse. We find that Gli activation is found in gliomas and correlates with grade. In addition, we find that sonic hedgehog (SHH) is expressed in these tumors and also correlates with grade. We identify microvascular proliferation and pseudopalisades, elements that define high-grade gliomas as SHH-producing microenvironments. We describe two populations of SHH-producing stromal cells that reside in perivascular niche (PVN), namely low-cycling astrocytes and endothelial cells. Using the Ptc-LacZ knock-in mouse as a second Gli responsive reporter, we show beta-galactosidase activity in the PVN and in some tumors diffusely throughout the tumor. Lastly, we observe that SHH is similarly expressed in human gliomas and note that an intact tumor microenvironment or neurosphere conditions in vitro are required for Gli activity.

Authors
Becher, OJ; Hambardzumyan, D; Fomchenko, EI; Momota, H; Mainwaring, L; Bleau, AM; Katz, AM; Edgar, M; Kenney, AM; Cordon-Cardo, C; Blasberg, RG; Holland, EC
MLA Citation
Becher, OJ, Hambardzumyan, D, Fomchenko, EI, Momota, H, Mainwaring, L, Bleau, AM, Katz, AM, Edgar, M, Kenney, AM, Cordon-Cardo, C, Blasberg, RG, and Holland, EC. "Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas." Cancer Res 68.7 (April 1, 2008): 2241-2249.
PMID
18381430
Source
pubmed
Published In
Cancer Research
Volume
68
Issue
7
Publish Date
2008
Start Page
2241
End Page
2249
DOI
10.1158/0008-5472.CAN-07-6350

PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo.

Medulloblastomas are brain tumors that arise in the cerebellum of children and contain stem cells in a perivascular niche thought to give rise to recurrence following radiation. We used several mouse models of medulloblastomas in parallel to better understand how the critical cell types in these tumors respond to therapy. In our models, the proliferating cells in the tumor bulk undergo radiation-induced, p53-dependent apoptotic cell death. Activation of Akt signaling via PTEN loss transforms these cells to a nonproliferating extensive nodularity morphology. By contrast, the nestin-expressing perivascular stem cells survive radiation, activate PI3K/Akt pathway, undergo p53-dependent cell cycle arrest, and re-enter the cell cycle at 72 h. Furthermore, the ability of these cells to induce p53 is dependent on the presence of PTEN. These cellular characteristics are similar to human medulloblastomas. Finally, inhibition of Akt signaling sensitizes cells in the perivascular region to radiation-induced apoptosis.

Authors
Hambardzumyan, D; Becher, OJ; Rosenblum, MK; Pandolfi, PP; Manova-Todorova, K; Holland, EC
MLA Citation
Hambardzumyan, D, Becher, OJ, Rosenblum, MK, Pandolfi, PP, Manova-Todorova, K, and Holland, EC. "PI3K pathway regulates survival of cancer stem cells residing in the perivascular niche following radiation in medulloblastoma in vivo." Genes Dev 22.4 (February 15, 2008): 436-448.
PMID
18281460
Source
pubmed
Published In
Genes & development
Volume
22
Issue
4
Publish Date
2008
Start Page
436
End Page
448
DOI
10.1101/gad.1627008

Medulloblastoma: therapy and biologic considerations.

Tremendous strides have been made in both the treatment and the biologic understanding of medulloblastoma. Present optimal treatment can cure most medulloblastoma patients. A substantial minority of patients, however, will have recurrent or progressive disease. Recent studies have demonstrated that the success of treatment is not simply a matter of chance, but rather can be predicted based on specific biologic markers. These markers predict outcome independent of clinical staging and make clear that medulloblastomas are a biologically diverse group of tumors with variable clinical behavior. Molecular biologic investigation, including replication of tumorigenesis in transgenic mice, has further elucidated the complex biology of medulloblastoma. Current standard and investigational treatments, however, do not yet make use of biologic markers that predict risk of recurrence. Practical limitations have slowed the pace at which treatment paradigms can be revised to incorporate biologic insights. Mouse medulloblastoma models may provide an important bridge between biologic investigation and the development of new therapeutic approaches.

Authors
Gershon, TR; Becher, OJ
MLA Citation
Gershon, TR, and Becher, OJ. "Medulloblastoma: therapy and biologic considerations." Curr Neurol Neurosci Rep 6.3 (May 2006): 200-206. (Review)
PMID
16635428
Source
pubmed
Published In
Current Neurology and Neuroscience Reports
Volume
6
Issue
3
Publish Date
2006
Start Page
200
End Page
206

Genetically engineered models have advantages over xenografts for preclinical studies.

Mouse models of human cancer are valuable tools for cancer research. Although xenografts and genetically engineered models (GEMs) possess limitations as well as advantages, each system plays a significant role in preclinical testing. Tumor xenografts are easy to use, relatively inexpensive, and reproducible. The main drawback of xenografts is that the genetics and histology of the tumors are frequently not representative of the respective human tumor and, thus far, these models have not been as predictive of therapeutic success as one would like. By contrast, GEMs are histologically and genetically accurate models of human cancer but have disadvantages of heterogeneity with regard to frequency, latency, and growth. These disadvantages are reminiscent of the variable behavior of actual human tumors. Recently, these shortcomings have been partly overcome with the development of anatomic and molecular in vivo imaging techniques such as magnetic resonance imaging and bioluminescence imaging. These new technologies will hopefully support the use of GEMs in preclinical trials and help determine if trials in GEMs are more predicative than xenografts of human responses.

Authors
Becher, OJ; Holland, EC
MLA Citation
Becher, OJ, and Holland, EC. "Genetically engineered models have advantages over xenografts for preclinical studies." Cancer Res 66.7 (April 1, 2006): 3355-3358.
PMID
16585152
Source
pubmed
Published In
Cancer Research
Volume
66
Issue
7
Publish Date
2006
Start Page
3355
End Page
3358
DOI
10.1158/0008-5472.CAN-05-3827

Erratum: Genetically engineered models have advantages over xenografts for preclinical studies (Cancer Research (April 1, 2006) 66 (3355-3359))

Authors
Becher, OJ; Holland, EC
MLA Citation
Becher, OJ, and Holland, EC. "Erratum: Genetically engineered models have advantages over xenografts for preclinical studies (Cancer Research (April 1, 2006) 66 (3355-3359))." Cancer Research 66.17 (2006): 8925--.
Source
scival
Published In
Cancer Research
Volume
66
Issue
17
Publish Date
2006
Start Page
8925-
DOI
10.1158/0008-5472.CAN-66-17-COR

Erratum: Genetically engineered models have advantages over xenografts for preclinical studies (Cancer Research (2006) 66 (3355-3359))

Authors
Becher, OJ; Holland, EC
MLA Citation
Becher, OJ, and Holland, EC. "Erratum: Genetically engineered models have advantages over xenografts for preclinical studies (Cancer Research (2006) 66 (3355-3359))." Cancer Research 66.10 (2006): 5526--.
Source
scival
Published In
Cancer Research
Volume
66
Issue
10
Publish Date
2006
Start Page
5526-
DOI
10.1158/1078-0432.CAN-66-10-COR

Contributions of human tumor xenografts to anticancer drug development: Response

Authors
Becher, OJ; Holland, EC
MLA Citation
Becher, OJ, and Holland, EC. "Contributions of human tumor xenografts to anticancer drug development: Response." Cancer Research 66.7 (2006): 3354--.
Source
scival
Published In
Cancer Research
Volume
66
Issue
7
Publish Date
2006
Start Page
3354-

Serial expression profiling of T98 glioblastoma cell line with and without exogenous recombinant IGFBP2 suggests its role in angiogenesis

Authors
Becher, OJ; Peterson, KM; Brown, KM; MacDonald, TJ
MLA Citation
Becher, OJ, Peterson, KM, Brown, KM, and MacDonald, TJ. "Serial expression profiling of T98 glioblastoma cell line with and without exogenous recombinant IGFBP2 suggests its role in angiogenesis." April 2003.
Source
wos-lite
Published In
Pediatric Research
Volume
53
Issue
4
Publish Date
2003
Start Page
272A
End Page
273A

Growth factors and their receptors in pediatric gliomas using microarray gene chips

Authors
Becher, OJ; Khatua, S; Lawlor, C; Chopra, A; Peterson, K; MacDonald, T
MLA Citation
Becher, OJ, Khatua, S, Lawlor, C, Chopra, A, Peterson, K, and MacDonald, T. "Growth factors and their receptors in pediatric gliomas using microarray gene chips." PEDIATRIC RESEARCH 51.4 (April 2002): 248A-248A.
Source
wos-lite
Published In
Pediatric Research
Volume
51
Issue
4
Publish Date
2002
Start Page
248A
End Page
248A

Reasons for pediatrician nonadherence to asthma guidelines.

BACKGROUND: The 1997 National Heart, Lung, and Blood Institute (NHLBI) asthma guidelines include recommendations on how to improve the quality of care for asthma. OBJECTIVE: To identify barriers to physician adherence to the NHLBI guidelines. DESIGN: Cross-sectional survey. PARTICIPANTS: A national random sample of 829 primary care pediatricians. MAIN OUTCOME MEASURES: Self-reported adherence to 4 components of the NHLBI guidelines (steroid prescription, instructing peak flow meter use, screening and counseling patients with asthma for smoking, and screening and counseling parents for smoking). We also collected information on physician demographics, practice characteristics, and possible barriers to adherence. We defined adherence as following a guideline component more than 90% of the time. RESULTS: The response rate was 55% (456/829). Most of the responding pediatricians were aware of the guidelines (88%) and reported having access to a copy of the guidelines (81%). Self-reported rates of adherence were between 39% and 53% for the guideline components. After controlling for demographics and other barriers, we found that nonadherence was associated with specific barriers for each guideline component: for corticosteroid prescription, lack of agreement (odds ratio [OR], 6.8; 95% confidence interval [CI], 3.2-14.4); for peak flow meter use, lack of self-efficacy (OR, 3.4; 95% CI, 1.9-6.1) and lack of outcome expectancy (OR, 4.7; 95% CI, 2.5-8.9); and for screening and counseling of patients and parents for smoking, lack of self-efficacy (OR, 3.8; 95% CI, 1.7-6.2 and OR, 2.8; 95% CI, 1.3-5.9, respectively). CONCLUSIONS: Although pediatricians in this sample were aware of the NHLBI guidelines, a variety of barriers precluded their successful use. To improve NHLBI guideline adherence, tailored interventions that address the barriers characteristic of a given guideline component need to be implemented.

Authors
Cabana, MD; Rand, CS; Becher, OJ; Rubin, HR
MLA Citation
Cabana, MD, Rand, CS, Becher, OJ, and Rubin, HR. "Reasons for pediatrician nonadherence to asthma guidelines." Arch Pediatr Adolesc Med 155.9 (September 2001): 1057-1062.
PMID
11529809
Source
pubmed
Published In
Archives of Pediatrics and Adolescent Medicine
Volume
155
Issue
9
Publish Date
2001
Start Page
1057
End Page
1062

Histiocytoid cardiomyopathy presenting with Wolff-Parkinson-White syndrome.

Authors
Cabana, MD; Becher, O; Smith, A
MLA Citation
Cabana, MD, Becher, O, and Smith, A. "Histiocytoid cardiomyopathy presenting with Wolff-Parkinson-White syndrome." Heart 83.1 (January 2000): 98-99.
PMID
10618346
Source
pubmed
Published In
Heart
Volume
83
Issue
1
Publish Date
2000
Start Page
98
End Page
99

Patellofemoral complications after total knee arthroplasty: a comparison of Modular Porous-Coated Anatomic with Duracon prostheses.

Clinical and radiographic analyses were used to compare results obtained in 45 patients who underwent a Modular Porous-Coated Anatomic total knee arthroplasty with results in a similar group of 45 patients who underwent a Duracon total knee arthroplasty. The surgeries were consecutively performed over an 8-month period, and follow-up evaluation averaged 63 months. The two patient groups were similar with regard to the following variables: age, sex, diagnosis, height, weight, and preoperative and postoperative activity levels. Whereas both Duracon and Modular total knee arthroplasty prostheses yielded similar results approximately 5 years after surgery, the data suggest that Duracon appears to minimize patellofemoral complications.

Authors
Mont, MA; Becher, OJ; Lee, CW; LaPorte, DM; Hungerford, DS
MLA Citation
Mont, MA, Becher, OJ, Lee, CW, LaPorte, DM, and Hungerford, DS. "Patellofemoral complications after total knee arthroplasty: a comparison of Modular Porous-Coated Anatomic with Duracon prostheses." Am J Orthop (Belle Mead NJ) 28.4 (April 1999): 241-247.
PMID
10220096
Source
pubmed
Published In
American Journal of Orthopedics
Volume
28
Issue
4
Publish Date
1999
Start Page
241
End Page
247
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