You are here

Nixon, Andrew Benjamin

Overview:

Andrew Nixon, PhD, MBA (Associate Professor of Medicine) is Director of the Phase I Biomarker Laboratory, which brings together clinical, translational and basic research to pursue the development of novel biomarkers defining mechanisms of sensitivity, resistance, and toxicity to given therapeutic drug classes, particularly anti-angiogenic agents. Additionally, the laboratory has been appointed as a Molecular Reference Laboratory for the Alliance oncology cooperative group, a national clinical trial research group sponsored by the National Cancer Institute. The laboratory has quality control procedures in place to address many of the issues involved in clinical trial research including determination of sample quantity, sample integrity, and sample heterogeneity. We have spent considerable time developing robust assays that utilize limited amounts of specimen while providing high quality data. Multiplex ELISA and gene expression arrays are used to analyze serially collected blood and paraffin samples archived from cancer patient clinical trials. This work has the potential to improve the efficacy and toxicity of current therapies and to guide the development of the next generation of anti-angiogenesis therapies for cancer and other diseases.

Positions:

Associate Professor in Medicine

Medicine, Medical Oncology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 1997

Ph.D. — Wake Forest University

Grants:

Preclinical and Human Correlative Studies of a Novel Bruton Tyronsine Kinase Inhibitor in Pancreatic Cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Department of Defense
Role
Co Investigator
Start Date
September 30, 2016
End Date
September 29, 2019

Dovitinib in Treating Patients with Recurrent or Progressive Glioblastoma

Administered By
Duke Cancer Institute
AwardedBy
Cleveland Clinic Foundation
Role
Principal Investigator
Start Date
September 15, 2015
End Date
December 31, 2018

The role of Claudin-2 in metastatic colorectal cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Seattle Genetics, Inc
Role
Principal Investigator
Start Date
July 25, 2016
End Date
May 05, 2018

Immune signatures in metastatic colorectal cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Genentech, Inc.
Role
Principal Investigator
Start Date
February 23, 2017
End Date
October 31, 2017

RAP-041 mediated modulation of intratumoral immune cell subpopulations in vivo and effect of combination treatment with anti-PD1 monoclonal antibody

Administered By
Medicine, Medical Oncology
AwardedBy
Acceleron Pharma
Role
Principal Investigator
Start Date
September 27, 2016
End Date
September 26, 2017

Anti-endoglin mediated modulation of intratumoral Immune Cell Subpopulationg in vivo and effoect of combination treatment with anti-PD1 monoclonal antibodies

Administered By
Duke Cancer Institute
AwardedBy
Tracon Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
September 11, 2015
End Date
September 11, 2017

CTOT - Cell Free DNA

Administered By
Medicine, Medical Oncology
AwardedBy
Mount Sinai School of Medicine
Role
Principal Investigator
Start Date
September 01, 2016
End Date
August 31, 2017

Predictive value of the IL6 pathway to direct anti-angiogenic therapy in advanced ovarian cancer

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
American Association of Obstetricians and Gynecologists Foundation
Role
Co Investigator
Start Date
July 27, 2017
End Date
July 29, 2017

Blood-based Biomarker Profiling for TEW-7197

Administered By
Medicine, Medical Oncology
AwardedBy
MedPacto, Inc
Role
Co Investigator
Start Date
May 04, 2016
End Date
May 03, 2017

Blood-based Angiome Profiling to Direct Bevacizumab Therapy in Ovarian Cancer

Administered By
Obstetrics and Gynecology, Gynecologic Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
May 01, 2014
End Date
April 30, 2017

Janssen Research AGreement

Administered By
Radiation Oncology
AwardedBy
Janssen Research & Development, LLC
Role
Co Investigator
Start Date
November 27, 2014
End Date
December 31, 2016

The prevalence of MET gene amplification in metastatic colorectal cancer

Administered By
Medicine, Medical Oncology
AwardedBy
Amgen, Inc.
Role
Principal Investigator
Start Date
November 25, 2014
End Date
November 24, 2016

Serum Biomarkers in Lymphoma

Administered By
Medicine, Medical Oncology
AwardedBy
Brigham and Women's Hospital
Role
Principal Investigator
Start Date
October 01, 2014
End Date
February 28, 2015

(PQA5) 'Dose and Mechanisms of Exercise in Breast Cancer Prevention'

Administered By
Radiation Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
September 23, 2013
End Date
February 14, 2014

Anti-VEGF in Tumors & Wounds: Efficacy vs Toxicity

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Co Investigator
Start Date
April 16, 2006
End Date
February 28, 2012

New Clinical Biomarker for Cancer--Wound Angiogenesis

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Assistant Research Professor
Start Date
July 01, 2000
End Date
January 31, 2006

Regulation Of Cyclic Gmp Phosphodiesterase By Gz

Administered By
Pharmacology & Cancer Biology
AwardedBy
National Institutes of Health
Role
PI-Fellow
Start Date
January 20, 1997
End Date
July 31, 2001
Show More

Publications:

Metastatic clear cell renal cell carcinoma: Circulating biomarkers to guide antiangiogenic and immune therapies.

The therapeutic armamentarium for metastatic renal cell carcinoma has rapidly expanded over the past decade to include a number of anti-angiogenic therapies and more recently, an immunotherapy. Biomarkers in the peripheral circulation are easily accessible, can provide important prognostic value, and have the potential to give important information about disease progression and treatment sensitivity or response.Herein, we review a variety of circulating markers including circulating protein markers (VEGF-A, inflammatory cytokines, and LDH), circulating nucleic acids (cell free DNA and micro RNAs), and circulating cellular factors (circulating tumor cells, circulating endothelial cells, and immune cell subsets). We discuss these biomarkers in the context of their ability to provide prognostic and predictive information to anti-angiogenic and immunotherapeutic agents.While promising, there is still much work to be done, and prospective evaluation of any potential predictive biomarker for these therapies is greatly needed.

Authors
Zhang, T; Zhu, J; George, DJ; Nixon, AB
MLA Citation
Zhang, T, Zhu, J, George, DJ, and Nixon, AB. "Metastatic clear cell renal cell carcinoma: Circulating biomarkers to guide antiangiogenic and immune therapies." Urologic oncology 34.11 (November 2016): 510-518.
PMID
27498927
Source
epmc
Published In
Urologic Oncology: Seminars and Original Investigations
Volume
34
Issue
11
Publish Date
2016
Start Page
510
End Page
518
DOI
10.1016/j.urolonc.2016.06.020

TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer in part due to inherent resistance to chemotherapy, including the first-line drug gemcitabine. Although low expression of the nucleoside transporters hENT1 and hCNT3 that mediate cellular uptake of gemcitabine has been linked to gemcitabine resistance, the mechanisms regulating their expression in the PDAC tumor microenvironment are largely unknown. Here, we report that the matricellular protein cysteine-rich angiogenic inducer 61 (CYR61) negatively regulates the nucleoside transporters hENT1 and hCNT3. CRISPR/Cas9-mediated knockout of CYR61 increased expression of hENT1 and hCNT3, increased cellular uptake of gemcitabine and sensitized PDAC cells to gemcitabine-induced apoptosis. In PDAC patient samples, expression of hENT1 and hCNT3 negatively correlates with expression of CYR61 We demonstrate that stromal pancreatic stellate cells (PSCs) are a source of CYR61 within the PDAC tumor microenvironment. Transforming growth factor-β (TGF-β) induces the expression of CYR61 in PSCs through canonical TGF-β-ALK5-Smad2/3 signaling. Activation of TGF-β signaling or expression of CYR61 in PSCs promotes resistance to gemcitabine in PDAC cells in an in vitro co-culture assay. Our results identify CYR61 as a TGF-β-induced stromal-derived factor that regulates gemcitabine sensitivity in PDAC and suggest that targeting CYR61 may improve chemotherapy response in PDAC patients.

Authors
Hesler, RA; Huang, JJ; Starr, MD; Treboschi, VM; Bernanke, AG; Nixon, AB; McCall, SJ; White, RR; Blobe, GC
MLA Citation
Hesler, RA, Huang, JJ, Starr, MD, Treboschi, VM, Bernanke, AG, Nixon, AB, McCall, SJ, White, RR, and Blobe, GC. "TGF-β-induced stromal CYR61 promotes resistance to gemcitabine in pancreatic ductal adenocarcinoma through downregulation of the nucleoside transporters hENT1 and hCNT3." Carcinogenesis (September 7, 2016).
PMID
27604902
Source
epmc
Published In
Carcinogenesis
Publish Date
2016

Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance).

Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin-binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment-by-marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild-type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild-type (WT) patients (chemo HR = 0.98, 95% CI = 0.74-1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05-2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02-2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67-1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68-13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31-2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88-1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32-1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab.

Authors
Hatch, AJ; Sibley, AB; Starr, MD; Brady, JC; Jiang, C; Jia, J; Bowers, DL; Pang, H; Owzar, K; Niedzwiecki, D; Innocenti, F; Venook, AP; Hurwitz, HI; Nixon, AB
MLA Citation
Hatch, AJ, Sibley, AB, Starr, MD, Brady, JC, Jiang, C, Jia, J, Bowers, DL, Pang, H, Owzar, K, Niedzwiecki, D, Innocenti, F, Venook, AP, Hurwitz, HI, and Nixon, AB. "Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance)." Cancer medicine 5.9 (September 2016): 2249-2260.
PMID
27465221
Source
epmc
Published In
Cancer Medicine
Volume
5
Issue
9
Publish Date
2016
Start Page
2249
End Page
2260
DOI
10.1002/cam4.806

Efficacy of the nanoparticle–drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I–IIa clinical trial

Authors
Keefe, SM; Hoffman-Censits, J; Cohen, RB; Mamtani, R; Heitjan, D; Eliasof, S; Nixon, A; Turnbull, B; Garmey, EG; Gunnarsson, O; Waliki, M; Ciconte, J; Jayaraman, L; Senderowicz, A; Tellez, AB; Hennessy, M; Piscitelli, A; Vaughn, D; Smith, A; Haas, NB
MLA Citation
Keefe, SM, Hoffman-Censits, J, Cohen, RB, Mamtani, R, Heitjan, D, Eliasof, S, Nixon, A, Turnbull, B, Garmey, EG, Gunnarsson, O, Waliki, M, Ciconte, J, Jayaraman, L, Senderowicz, A, Tellez, AB, Hennessy, M, Piscitelli, A, Vaughn, D, Smith, A, and Haas, NB. "Efficacy of the nanoparticle–drug conjugate CRLX101 in combination with bevacizumab in metastatic renal cell carcinoma: results of an investigator-initiated phase I–IIa clinical trial." Annals of Oncology 27.8 (August 2016): 1579-1585.
Source
crossref
Published In
Annals of Oncology
Volume
27
Issue
8
Publish Date
2016
Start Page
1579
End Page
1585
DOI
10.1093/annonc/mdw188

Abstract 3388: Genetic prediction of VEGF-A plasma levels in cancer patients

Authors
Innocenti, F; Jiang, C; Sibley, A; Etheridge, A; Furukawa, Y; Kubo, M; Kindler, HL; Venook, AP; Hurwitz, HI; Nixon, AB; Owzar, K
MLA Citation
Innocenti, F, Jiang, C, Sibley, A, Etheridge, A, Furukawa, Y, Kubo, M, Kindler, HL, Venook, AP, Hurwitz, HI, Nixon, AB, and Owzar, K. "Abstract 3388: Genetic prediction of VEGF-A plasma levels in cancer patients." July 15, 2016.
Source
crossref
Published In
Cancer Research
Volume
76
Issue
14 Supplement
Publish Date
2016
Start Page
3388
End Page
3388
DOI
10.1158/1538-7445.AM2016-3388

HIF inhibition in metastatic renal cell carcinoma (RCC): FINAL results from a phase 1-2a clinical trial evaluating the nanoparticle-drug conjugate, CRLX101, in combination with bevacizumab

Authors
Keefe, SM; Hoffman-Censits, J; Cohen, RB; Eliasof, S; Garmey, EG; Gunnarsson, O; Hennessy, M; Jayaraman, L; Mamtani, R; Mannan, AM; Nixon, AB; Piscitelli, A; Robinson, J; Smith, A; Tellez, AB; Vaughn, D; Walicki, M; Haas, NB
MLA Citation
Keefe, SM, Hoffman-Censits, J, Cohen, RB, Eliasof, S, Garmey, EG, Gunnarsson, O, Hennessy, M, Jayaraman, L, Mamtani, R, Mannan, AM, Nixon, AB, Piscitelli, A, Robinson, J, Smith, A, Tellez, AB, Vaughn, D, Walicki, M, and Haas, NB. "HIF inhibition in metastatic renal cell carcinoma (RCC): FINAL results from a phase 1-2a clinical trial evaluating the nanoparticle-drug conjugate, CRLX101, in combination with bevacizumab." December 2015.
Source
wos-lite
Published In
Bju International
Volume
116
Publish Date
2015
Start Page
10
End Page
11

A Molecular Model for Predicting Overall Survival in Patients with Metastatic Clear Cell Renal Carcinoma: Results from CALGB 90206 (Alliance).

Prognosis associated with metastatic renal cell carcinoma (mRCC) can vary widely.This study used pretreatment nephrectomy specimens from a randomized phase III trial. Expression levels of candidate genes were determined from archival tumors using the OpenArray® platform for TaqMan® RT-qPCR. The dataset was randomly divided at 2:1 ratio into training (n = 221) and testing (n = 103) sets to develop a multigene prognostic signature.Gene expressions were measured in 324 patients. In the training set, multiple models testing 424 candidate genes identified a prognostic signature containing 8 genes plus MSKCC clinical risk factors. In the testing set, the time dependent (td) AUC for a prognostic model containing the 8 genes with and without MSKCC risk factors were 0.72 and 0.69, respectively. The tdAUC for the clinical risk factors alone was 0.61. Additional primary mRCCs from patients with mRCC (n = 12) were sampled in multiple sites and standard deviations of gene expressions within a tumor were used as a measure of heterogeneity. All 8 genes in the final prognostic model met our criteria for minimal heterogeneity.A molecular prognostic signature based on 8 genes was developed and is ready for external validation in this patient population and other related settings such as nonmetastatic RCC.

Authors
Kim, HL; Halabi, S; Li, P; Mayhew, G; Simko, J; Nixon, AB; Small, EJ; Rini, B; Morris, MJ; Taplin, M-E; George, D
MLA Citation
Kim, HL, Halabi, S, Li, P, Mayhew, G, Simko, J, Nixon, AB, Small, EJ, Rini, B, Morris, MJ, Taplin, M-E, and George, D. "A Molecular Model for Predicting Overall Survival in Patients with Metastatic Clear Cell Renal Carcinoma: Results from CALGB 90206 (Alliance)." EBioMedicine 2.11 (November 2015): 1814-1820.
PMID
26870806
Source
epmc
Published In
EBioMedicine
Volume
2
Issue
11
Publish Date
2015
Start Page
1814
End Page
1820
DOI
10.1016/j.ebiom.2015.09.012

Direct Evidence of Target Inhibition with Anti-VEGF, EGFR, and mTOR Therapies in a Clinical Model of Wound Healing.

In early clinical testing, most novel targeted anticancer therapies have limited toxicities and limited efficacy, which complicates dose and schedule selection for these agents. Confirmation of target inhibition is critical for rational drug development; however, repeated tumor biopsies are often impractical and peripheral blood mononuclear cells and normal skin are often inadequate surrogates for tumor tissue. Based upon the similarities of tumor and wound stroma, we have developed a clinical dermal granulation tissue model to evaluate novel targeted therapies.A 4-mm skin punch biopsy was used to stimulate wound healing and a repeat 5-mm punch biopsy was used to harvest the resulting granulation tissue. This assay was performed at pretreatment and on-treatment evaluating four targeted therapies, bevacizumab, everolimus, erlotinib, and panitumumab, in the context of three different clinical trials. Total and phosphorylated levels VEGFR2, S6RP, and EGFR were evaluated using ELISA-based methodologies.Significant and consistent inhibition of the VEGF pathway (using VEGFR2 as the readout) was observed in granulation tissue biopsies from patients treated with bevacizumab and everolimus. In addition, significant and consistent inhibition of the mTOR pathway (using S6RP as the readout) was observed in patients treated with everolimus. Finally, significant inhibition of the EGFR pathway (using EGFR as the readout) was observed in patients treated with panitumumab, but this was not observed in patients treated with erlotinib.Molecular analyses of dermal granulation tissue can be used as a convenient and quantitative pharmacodynamic biomarker platform for multiple classes of targeted therapies.

Authors
Jia, J; Dellinger, AE; Weiss, ES; Bulusu, A; Rushing, C; Li, H; Howard, LA; Kaplan, N; Pang, H; Hurwitz, HI; Nixon, AB
MLA Citation
Jia, J, Dellinger, AE, Weiss, ES, Bulusu, A, Rushing, C, Li, H, Howard, LA, Kaplan, N, Pang, H, Hurwitz, HI, and Nixon, AB. "Direct Evidence of Target Inhibition with Anti-VEGF, EGFR, and mTOR Therapies in a Clinical Model of Wound Healing." Clinical cancer research : an official journal of the American Association for Cancer Research 21.15 (August 2015): 3442-3452.
PMID
25878330
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
15
Publish Date
2015
Start Page
3442
End Page
3452
DOI
10.1158/1078-0432.ccr-14-2819

Identifying Blood-Based Protein Biomarkers for Antiangiogenic Agents in the Clinic: A Decade of Progress.

Agents that inhibit tumor angiogenesis are widely used and have provided meaningful survival benefits to patients in multiple disease settings. However, these agents differ significantly in their mechanisms of action and potential toxicities, and there are currently no prospectively validated biomarkers to guide the selection of agents for individual patients. Blood-based protein biomarkers are well suited for trials investigating antiangiogenic agents for multiple reasons. Many elements of the molecular pathways that antiangiogenic agents target are present and detectable in the circulation, sample collection is minimally invasive, and samples can be collected throughout the course of treatment. Blood-based biomarkers for antiangiogenic therapies are urgently needed to guide the development of therapeutic strategies. This review provides a brief summary of the current blood-based protein biomarkers for antiangiogenic therapies.

Authors
Hatch, AJ; Clarke, JM; Nixon, AB; Hurwitz, HI
MLA Citation
Hatch, AJ, Clarke, JM, Nixon, AB, and Hurwitz, HI. "Identifying Blood-Based Protein Biomarkers for Antiangiogenic Agents in the Clinic: A Decade of Progress." Cancer journal (Sudbury, Mass.) 21.4 (July 2015): 322-326.
PMID
26222085
Source
epmc
Published In
Cancer Journal
Volume
21
Issue
4
Publish Date
2015
Start Page
322
End Page
326
DOI
10.1097/ppo.0000000000000129

HER3 as a biomarker of prognosis and panitumumab (Pan) benefit in RAS-wt advanced colorectal cancer (aCRC)

Authors
Seligmann, JF; Elliott, F; Jacobs, B; Hatch, AJ; Sibley, A; Richman, S; Jiang, C; Barrett, J; Owzar, K; Quirke, P; Hurwitz, H; Seymour, MT; Nixon, AB
MLA Citation
Seligmann, JF, Elliott, F, Jacobs, B, Hatch, AJ, Sibley, A, Richman, S, Jiang, C, Barrett, J, Owzar, K, Quirke, P, Hurwitz, H, Seymour, MT, and Nixon, AB. "HER3 as a biomarker of prognosis and panitumumab (Pan) benefit in RAS-wt advanced colorectal cancer (aCRC)." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Phase II trial of dovitinib in recurrent glioblastoma.

Authors
Ahluwalia, MS; Papadantonakis, N; Venur, VA; Schilero, C; Peereboom, DM; Stevens, G; Rosenfeld, S; Vogelbaum, MA; Elson, P; Nixon, AB; McCrae, K
MLA Citation
Ahluwalia, MS, Papadantonakis, N, Venur, VA, Schilero, C, Peereboom, DM, Stevens, G, Rosenfeld, S, Vogelbaum, MA, Elson, P, Nixon, AB, and McCrae, K. "Phase II trial of dovitinib in recurrent glioblastoma." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

HIF inhibition in metastatic renal cell carcinoma (mRCC): Final results of a phase Ib/IIa clinical trial evaluating the nanoparticle drug conjugate (NDC), CRLX101, in combination with bevacizumab (bev).

Authors
Keefe, SM; Hoffman-Censits, JH; Mamtani, R; Walicki, M; Robinson, J; Smith, A; Gunnarsson, O; Piscitelli, A; Hennessey, M; Jayaraman, L; Nixon, AB; Eliasof, S; Cohen, RB; Vaughn, DJ; Garmey, EG; Haas, NB
MLA Citation
Keefe, SM, Hoffman-Censits, JH, Mamtani, R, Walicki, M, Robinson, J, Smith, A, Gunnarsson, O, Piscitelli, A, Hennessey, M, Jayaraman, L, Nixon, AB, Eliasof, S, Cohen, RB, Vaughn, DJ, Garmey, EG, and Haas, NB. "HIF inhibition in metastatic renal cell carcinoma (mRCC): Final results of a phase Ib/IIa clinical trial evaluating the nanoparticle drug conjugate (NDC), CRLX101, in combination with bevacizumab (bev)." May 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
15
Publish Date
2015

Biomarker signatures correlate with clinical outcome in refractory metastatic colorectal cancer patients receiving bevacizumab and everolimus.

A novel combination of bevacizumab and everolimus was evaluated in refractory colorectal cancer patients in a phase II trial. In this retrospective analysis, plasma samples from 49 patients were tested for over 40 biomarkers at baseline and after one or two cycles of drug administration. Analyte levels at baseline and change on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) using univariate Cox proportional hazard modeling. Multivariable analyses were conducted using Cox modeling. Significant changes in multiple markers were observed following bevacizumab and everolimus treatment. Baseline levels of six markers significantly correlated with PFS and OS, including CRP, Gro-α, IGFBP-1, TF, ICAM-1, and TSP-2 (P < 0.05). At C2D1, changes of IGFBP-3, TGFβ-R3, and IGFBP-2 correlated with PFS and OS. Prognostic models were developed for OS and PFS (P = 0.0002 and 0.004, respectively). The baseline model for OS consisted of CRP, Gro-α, and TF, while the on-treatment model at C2D1 included IGFBP-2, IGFBP-3, and TGFβ-R3. These data demonstrated that multiple biomarkers were significantly modulated in response to bevacizumab and everolimus. Several markers correlated with both PFS and OS. Interestingly, these markers are known to be associated with inflammation and IGF signaling, key modulators of mTOR biology.

Authors
Liu, Y; Starr, MD; Brady, JC; Rushing, C; Bulusu, A; Pang, H; Honeycutt, W; Amara, A; Altomare, I; Uronis, HE; Hurwitz, HI; Nixon, AB
MLA Citation
Liu, Y, Starr, MD, Brady, JC, Rushing, C, Bulusu, A, Pang, H, Honeycutt, W, Amara, A, Altomare, I, Uronis, HE, Hurwitz, HI, and Nixon, AB. "Biomarker signatures correlate with clinical outcome in refractory metastatic colorectal cancer patients receiving bevacizumab and everolimus." Molecular cancer therapeutics 14.4 (April 2015): 1048-1056.
PMID
25695956
Source
epmc
Published In
Molecular cancer therapeutics
Volume
14
Issue
4
Publish Date
2015
Start Page
1048
End Page
1056
DOI
10.1158/1535-7163.mct-14-0923-t

Gene expression markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance).

Formalin-fixed, paraffin-embedded tumor samples from CALGB 80203 were analyzed for expression of EGFR axis-related genes to identify prognostic or predictive biomarkers for cetuximab treatment.Patients (238 total) with first-line metastatic colorectal cancer (mCRC) were randomized to FOLFOX or FOLFIRI chemotherapy ± cetuximab. qRT-PCR analyses were conducted on tissues from 103 patients at baseline to measure gene expression levels of HER-related genes, including amphiregulin (AREG), betacellulin (BTC), NT5E (CD73), DUSP4, EGF, EGFR, epigen (EPGN), epiregulin (EREG), HBEGF, ERBB2 (HER2), ERBB3 (HER3), ERBB4 (HER4), PHLDA1, and TGFA. The interactions between expression levels and treatment with respect to progression-free survival (PFS) and overall survival (OS) were modeled using multiplicative Cox proportional hazards models.High tumor mRNA levels of HER2 [hazard ratio (HR), 0.64; P = 0.002] and EREG (HR, 0.89; P = 0.016) were prognostic markers associated with longer PFS across all patients. HER3 and CD73 expression levels were identified as potential predictive markers of benefit from cetuximab. In KRAS wild-type (WT) tumors, low HER3 expression was associated with longer OS from cetuximab treatment, whereas high HER3 expression was associated with shorter OS from cetuximab treatment (chemo + cetuximab: HR, 1.15; chemo-only: HR, 0.48; Pinteraction = 0.029). High CD73 expression was associated with longer PFS from cetuximab treatment in patients with KRAS-WT (chemo + cetuximab: HR, 0.91; chemo-only: HR, 1.57; Pinteraction = 0.026) and KRAS-mutant (Mut) tumors (chemo + cetuximab: HR, 0.80; chemo-only: HR, 1.29; P = 0.025).Gene expression of HER3 and CD73 was identified as a potential predictive marker for cetuximab. These data implicate HER axis signaling and immune modulation as potential mechanisms of cetuximab action and sensitivity.

Authors
Cushman, SM; Jiang, C; Hatch, AJ; Shterev, I; Sibley, AB; Niedzwiecki, D; Venook, AP; Owzar, K; Hurwitz, HI; Nixon, AB
MLA Citation
Cushman, SM, Jiang, C, Hatch, AJ, Shterev, I, Sibley, AB, Niedzwiecki, D, Venook, AP, Owzar, K, Hurwitz, HI, and Nixon, AB. "Gene expression markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance)." Clinical cancer research : an official journal of the American Association for Cancer Research 21.5 (March 2015): 1078-1086.
PMID
25520391
Source
epmc
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
21
Issue
5
Publish Date
2015
Start Page
1078
End Page
1086
DOI
10.1158/1078-0432.ccr-14-2313

A Phase I/biomarker study of bevacizumab in combination with CNTO 95 in patients with advanced solid tumors.

PURPOSE: Inhibition of tumor angiogenesis is an effective mechanism to limit tumor growth; dual inhibition may result in additional benefit. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF), and intetumumab is a fully humanized monoclonal antibody that blocks αv integrins when complexed with β integrins. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus intetumumab in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. METHODS: Patients with refractory solid tumors, Karnofsky performance status ≥70%, and adequate organ function were eligible. Plasma samples and wound biopsies were obtained at baseline and on-treatment. RESULTS: Twelve patients were enrolled and received study drug. No tumor responses were noted. Observed toxicities included three cases of transient uveitis likely related to intetumumab and one case of reversible posterior leukoencephalopathy syndrome likely related to bevacizumab. Biomarker analysis revealed changes in soluble endoglin, soluble E-cadherin, and soluble E-selectin as well as PlGF and VEGF-D while on treatment. There was no observed impact of bevacizumab plus intetumumab on the phosphorylated or total levels of paxillin in wound tissue; however, an increase in the ratio of phospho/total paxillin levels was noted. CONCLUSIONS: Bevacizumab and intetumumab can be administered safely in combination. Bevacizumab plus intetumumab treatment resulted in changes in the plasma levels of several extracellular matrix interacting proteins and angiogenic factors.

Authors
Uronis, HE; Jia, J; Bendell, JC; Howard, L; Ready, NA; Lee, PH; Starr, MD; Dellinger, A; Pang, H; Nixon, AB; Hurwitz, HI
MLA Citation
Uronis, HE, Jia, J, Bendell, JC, Howard, L, Ready, NA, Lee, PH, Starr, MD, Dellinger, A, Pang, H, Nixon, AB, and Hurwitz, HI. "A Phase I/biomarker study of bevacizumab in combination with CNTO 95 in patients with advanced solid tumors." Cancer chemotherapy and pharmacology 75.2 (February 2015): 343-352.
PMID
25527204
Source
epmc
Published In
Cancer Chemotherapy and Pharmacology
Volume
75
Issue
2
Publish Date
2015
Start Page
343
End Page
352
DOI
10.1007/s00280-014-2647-x

A leave-one-out cross-validation SAS macro for the identification of markers associated with survival.

A proper internal validation is necessary for the development of a reliable and reproducible prognostic model for external validation. Variable selection is an important step for building prognostic models. However, not many existing approaches couple the ability to specify the number of covariates in the model with a cross-validation algorithm. We describe a user-friendly SAS macro that implements a score selection method and a leave-one-out cross-validation approach. We discuss the method and applications behind this algorithm, as well as details of the SAS macro.

Authors
Rushing, C; Bulusu, A; Hurwitz, HI; Nixon, AB; Pang, H
MLA Citation
Rushing, C, Bulusu, A, Hurwitz, HI, Nixon, AB, and Pang, H. "A leave-one-out cross-validation SAS macro for the identification of markers associated with survival." Computers in biology and medicine 57 (February 2015): 123-129.
PMID
25553357
Source
epmc
Published In
Computers in Biology and Medicine
Volume
57
Publish Date
2015
Start Page
123
End Page
129
DOI
10.1016/j.compbiomed.2014.11.015

Coagulation factors in citrated plasma predict for benefit from bevacizumab (B) in patients with advanced pancreatic cancer (APC): Results from CALGB 80303 (Alliance)

Authors
Clarke, JM; Pang, H; Starr, MD; Hatch, AJ; Kindler, HL; O'Reilly, EM; Innocenti, F; Venook, AP; Hurwitz, H; Nixon, AB
MLA Citation
Clarke, JM, Pang, H, Starr, MD, Hatch, AJ, Kindler, HL, O'Reilly, EM, Innocenti, F, Venook, AP, Hurwitz, H, and Nixon, AB. "Coagulation factors in citrated plasma predict for benefit from bevacizumab (B) in patients with advanced pancreatic cancer (APC): Results from CALGB 80303 (Alliance)." January 20, 2015.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
33
Issue
3
Publish Date
2015

A Phase I/biomarker study of bevacizumab in combination with CNTO 95 in patients with advanced solid tumors

© Springer-Verlag 2014.Purpose: Inhibition of tumor angiogenesis is an effective mechanism to limit tumor growth; dual inhibition may result in additional benefit. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor (VEGF), and intetumumab is a fully humanized monoclonal antibody that blocks αv integrins when complexed with β integrins. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus intetumumab in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. Methods: Patients with refractory solid tumors, Karnofsky performance status ≥70 %, and adequate organ function were eligible. Plasma samples and wound biopsies were obtained at baseline and on-treatment. Results: Twelve patients were enrolled and received study drug. No tumor responses were noted. Observed toxicities included three cases of transient uveitis likely related to intetumumab and one case of reversible posterior leukoencephalopathy syndrome likely related to bevacizumab. Biomarker analysis revealed changes in soluble endoglin, soluble E-cadherin, and soluble E-selectin as well as PlGF and VEGF-D while on treatment. There was no observed impact of bevacizumab plus intetumumab on the phosphorylated or total levels of paxillin in wound tissue; however, an increase in the ratio of phospho/total paxillin levels was noted. Conclusions: Bevacizumab and intetumumab can be administered safely in combination. Bevacizumab plus intetumumab treatment resulted in changes in the plasma levels of several extracellular matrix interacting proteins and angiogenic factors.

Authors
Uronis, HE; Jia, J; Bendell, JC; Howard, L; Ready, NA; Lee, PH; Starr, MD; Dellinger, A; Pang, H; Nixon, AB; Hurwitz, HI
MLA Citation
Uronis, HE, Jia, J, Bendell, JC, Howard, L, Ready, NA, Lee, PH, Starr, MD, Dellinger, A, Pang, H, Nixon, AB, and Hurwitz, HI. "A Phase I/biomarker study of bevacizumab in combination with CNTO 95 in patients with advanced solid tumors." Cancer Chemotherapy and Pharmacology 75.2 (January 1, 2015): 343-352.
Source
scopus
Published In
Cancer Chemotherapy and Pharmacology
Volume
75
Issue
2
Publish Date
2015
Start Page
343
End Page
352
DOI
10.1007/s00280-014-2647-x

The search for biomarkers to direct antiangiogenic treatment in epithelial ovarian cancer.

Antiangiogenic agents have demonstrated improved progression-free survival in women with primary and recurrent epithelial ovarian cancer (EOC). Biomarkers that predict outcomes in patients treated with antiangiogenic agents are being investigated to rationally direct therapy for women most likely to benefit from these agents. Among the most promising plasma-based biomarkers are vascular endothelial growth factor (VEGF)-A, fibroblast growth factor, platelet-derived growth factor, angiopoietin-2, and VEGF receptor-2. While these biomarkers have been correlated with prognosis, they have not been shown to predict benefit, specifically from anti-VEGF therapy, highlighting the need for alternative biomarkers, including molecular and clinical factors, which may be predictive of outcome in women with ovarian cancer treated with antiangiogenic agents. Biomarkers are currently being investigated as secondary outcomes in several ongoing phase II and phase III clinical trials of antiangiogenic agents in patients with EOC. Molecular techniques, such as microarray analyses, and imaging techniques, such as dynamic contrast-enhanced magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography, are also being explored in this field. In this review, we provide a comprehensive overview of current biomarker research, with an emphasis on angiogenic biomarkers associated with EOC.

Authors
Secord, AA; Nixon, AB; Hurwitz, HI
MLA Citation
Secord, AA, Nixon, AB, and Hurwitz, HI. "The search for biomarkers to direct antiangiogenic treatment in epithelial ovarian cancer." Gynecologic oncology 135.2 (November 2014): 349-358.
PMID
25178997
Source
epmc
Published In
Gynecologic Oncology
Volume
135
Issue
2
Publish Date
2014
Start Page
349
End Page
358
DOI
10.1016/j.ygyno.2014.08.033

Abstract 2674: Stroma biology identifies heparins as differentiating agents in neuroblastoma

Authors
Knelson, EH; Gaviglio, AL; Nee, JC; Starr, MD; Nixon, AB; Marcus, SG; Blobe, GC
MLA Citation
Knelson, EH, Gaviglio, AL, Nee, JC, Starr, MD, Nixon, AB, Marcus, SG, and Blobe, GC. "Abstract 2674: Stroma biology identifies heparins as differentiating agents in neuroblastoma." October 1, 2014.
Source
crossref
Published In
Cancer Research
Volume
74
Issue
19 Supplement
Publish Date
2014
Start Page
2674
End Page
2674
DOI
10.1158/1538-7445.AM2014-2674

Effects of the combination of TRC105 and bevacizumab on endothelial cell biology.

Endoglin, or CD105, is a cell membrane glycoprotein that is overexpressed on proliferating endothelial cells (EC), including those found in malignancies and choroidal neovascularization. Endoglin mediates the transition from quiescent endothelium, characterized by the relatively dominant state of Smad 2/3 phosphorylation, to active angiogenesis by preferentially phosphorylating Smad 1/5/8. The monoclonal antibody TRC105 binds endoglin with high avidity and is currently being tested in phase 1b and phase 2 clinical trials. In this report, we evaluated the effects of TRC105 on primary human umbilical vascular endothelial cells (HUVEC) as a single agent and in combination with bevacizumab. As single agents, both TRC105 and bevacizumab efficiently blocked HUVEC tube formation, and the combination of both agents achieved even greater levels of inhibition. We further assessed the effects of each drug on various aspects of HUVEC function. While bevacizumab was observed to inhibit HUVEC viability in nutrient-limited medium, TRC105 had little effect on HUVEC viability, either alone or in combination with bevacizumab. Additionally, both drugs inhibited HUVEC migration and induced apoptosis. At the molecular level, TRC105 treatment of HUVEC lead to decreased Smad 1/5/8 phosphorylation in response to BMP-9, a primary ligand for endoglin. Together, these results indicate that TRC105 acts as an effective anti-angiogenic agent alone and in combination with bevacizumab.

Authors
Liu, Y; Tian, H; Blobe, GC; Theuer, CP; Hurwitz, HI; Nixon, AB
MLA Citation
Liu, Y, Tian, H, Blobe, GC, Theuer, CP, Hurwitz, HI, and Nixon, AB. "Effects of the combination of TRC105 and bevacizumab on endothelial cell biology." Investigational new drugs 32.5 (October 2014): 851-859.
PMID
24994097
Source
epmc
Published In
Investigational New Drugs
Volume
32
Issue
5
Publish Date
2014
Start Page
851
End Page
859
DOI
10.1007/s10637-014-0129-y

A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma.

Vatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC).A phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC.We evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability (> 1 year) was demonstrated in 19% of patients.Relevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC.

Authors
Bitting, RL; Healy, P; Creel, PA; Turnbull, J; Morris, K; Wood, SY; Hurwitz, HI; Starr, MD; Nixon, AB; Armstrong, AJ; George, DJ
MLA Citation
Bitting, RL, Healy, P, Creel, PA, Turnbull, J, Morris, K, Wood, SY, Hurwitz, HI, Starr, MD, Nixon, AB, Armstrong, AJ, and George, DJ. "A phase Ib study of combined VEGFR and mTOR inhibition with vatalanib and everolimus in patients with advanced renal cell carcinoma." Clinical genitourinary cancer 12.4 (August 2014): 241-250.
PMID
24685058
Source
epmc
Published In
Clinical genitourinary cancer
Volume
12
Issue
4
Publish Date
2014
Start Page
241
End Page
250
DOI
10.1016/j.clgc.2013.11.020

Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors.

To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients.This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms.Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival.Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m(2) BID days 1-14; oxaliplatin 100 mg/m(2) and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC.

Authors
Rangwala, F; Bendell, JC; Kozloff, MF; Arrowood, CC; Dellinger, A; Meadows, J; Tourt-Uhlig, S; Murphy, J; Meadows, KL; Starr, A; Broderick, S; Brady, JC; Cushman, SM; Morse, MA; Uronis, HE; Hsu, SD; Zafar, SY; Wallace, J; Starodub, AN; Strickler, JH; Pang, H; Nixon, AB; Hurwitz, HI
MLA Citation
Rangwala, F, Bendell, JC, Kozloff, MF, Arrowood, CC, Dellinger, A, Meadows, J, Tourt-Uhlig, S, Murphy, J, Meadows, KL, Starr, A, Broderick, S, Brady, JC, Cushman, SM, Morse, MA, Uronis, HE, Hsu, SD, Zafar, SY, Wallace, J, Starodub, AN, Strickler, JH, Pang, H, Nixon, AB, and Hurwitz, HI. "Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors." Investigational new drugs 32.4 (August 2014): 700-709.
PMID
24711126
Source
epmc
Published In
Investigational New Drugs
Volume
32
Issue
4
Publish Date
2014
Start Page
700
End Page
709
DOI
10.1007/s10637-014-0089-2

Role of TGF-β receptor III localization in polarity and breast cancer progression.

The majority of breast cancers originate from the highly polarized luminal epithelial cells lining the breast ducts. However, cell polarity is often lost during breast cancer progression. The type III transforming growth factor-β cell surface receptor (TβRIII) functions as a suppressor of breast cancer progression and also regulates the process of epithelial-to-mesenchymal transition (EMT), a consequence of which is the loss of cell polarity. Many cell surface proteins exhibit polarized expression, being targeted specifically to the apical or basolateral domains. Here we demonstrate that TβRIII is basolaterally localized in polarized breast epithelial cells and that disruption of the basolateral targeting of TβRIII through a single amino acid mutation of proline 826 in the cytosolic domain results in global loss of cell polarity through enhanced EMT. In addition, the mistargeting of TβRIII results in enhanced proliferation, migration, and invasion in vitro and enhanced tumor formation and invasion in an in vivo mouse model of breast carcinoma. These results suggest that proper localization of TβRIII is critical for maintenance of epithelial cell polarity and phenotype and expand the mechanisms by which TβRIII prevents breast cancer initiation and progression.

Authors
Meyer, AE; Gatza, CE; How, T; Starr, M; Nixon, AB; Blobe, GC
MLA Citation
Meyer, AE, Gatza, CE, How, T, Starr, M, Nixon, AB, and Blobe, GC. "Role of TGF-β receptor III localization in polarity and breast cancer progression." Molecular biology of the cell 25.15 (August 2014): 2291-2304.
PMID
24870032
Source
epmc
Published In
Molecular Biology of the Cell
Volume
25
Issue
15
Publish Date
2014
Start Page
2291
End Page
2304
DOI
10.1091/mbc.e14-03-0825

Ectodomain shedding of TβRIII is required for TβRIII-mediated suppression of TGF-β signaling and breast cancer migration and invasion.

The type III transforming growth factor β (TGF-β) receptor (TβRIII), also known as betaglycan, is the most abundantly expressed TGF-β receptor. TβRIII suppresses breast cancer progression by inhibiting migration, invasion, metastasis, and angiogenesis. TβRIII binds TGF-β ligands, with membrane-bound TβRIII presenting ligand to enhance TGF-β signaling. However, TβRIII can also undergo ectodomain shedding, releasing soluble TβRIII, which binds and sequesters ligand to inhibit downstream signaling. To investigate the relative contributions of soluble and membrane-bound TβRIII on TGF-β signaling and breast cancer biology, we defined TβRIII mutants with impaired (ΔShed-TβRIII) or enhanced ectodomain shedding (SS-TβRIII). Inhibiting ectodomain shedding of TβRIII increased TGF-β responsiveness and abrogated TβRIII's ability to inhibit breast cancer cell migration and invasion. Conversely, expressing SS-TβRIII, which increased soluble TβRIII production, decreased TGF-β signaling and increased TβRIII-mediated inhibition of breast cancer cell migration and invasion. Of importance, SS-TβRIII-mediated increases in soluble TβRIII production also reduced breast cancer metastasis in vivo. Taken together, these studies suggest that the ratio of soluble TβRIII to membrane-bound TβRIII is an important determinant for regulation of TβRIII- and TGF-β-mediated signaling and biology.

Authors
Elderbroom, JL; Huang, JJ; Gatza, CE; Chen, J; How, T; Starr, M; Nixon, AB; Blobe, GC
MLA Citation
Elderbroom, JL, Huang, JJ, Gatza, CE, Chen, J, How, T, Starr, M, Nixon, AB, and Blobe, GC. "Ectodomain shedding of TβRIII is required for TβRIII-mediated suppression of TGF-β signaling and breast cancer migration and invasion." Molecular biology of the cell 25.16 (August 2014): 2320-2332.
PMID
24966170
Source
epmc
Published In
Molecular Biology of the Cell
Volume
25
Issue
16
Publish Date
2014
Start Page
2320
End Page
2332
DOI
10.1091/mbc.e13-09-0524

Integrative pathway analysis using Graph-Based learning with applications to TCGA colon and ovarian data

Recent method development has included multi-dimensional genomic data algorithms because such methods have more accurately pre-dicted clinical phenotypes related to disease. This study is the first to conduct an integrative genomic pathway-based analysis with a graph-based learning algorithm. The methodology of this analysis, graph-based semi-supervised learning, detects pathways that improve prediction of a dichotomous variable, which in this study is cancer stage. This analysis integrates genome-level gene expression, methylation, and single nucleotide polymorphism (SNP) data in serous cystadenocarcinoma (OV) and colon adenocarcinoma (COAD). The top 10 ranked predictive pathways in COAD and OV were biologically relevant to their respective cancer stages and significantly enhanced prediction accuracy and area under the ROC curve (AUC) when compared to single data-type analyses. This method is an effective way to simultaneously predict binary clinical phenotypes and discover their biological mechanisms. © the authors, publisher and licensee Libertas Academica Limited.

Authors
Dellinger, AE; Nixon, AB; Pang, H
MLA Citation
Dellinger, AE, Nixon, AB, and Pang, H. "Integrative pathway analysis using Graph-Based learning with applications to TCGA colon and ovarian data." Cancer Informatics 13.SUPPL.4 (July 28, 2014).
Source
scopus
Published In
Cancer Informatics
Volume
13
Issue
SUPPL.4
Publish Date
2014
DOI
10.4137/CIN.S13634

Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth.

Neuroblastoma prognosis is dependent on both the differentiation state and stromal content of the tumor. Neuroblastoma tumor stroma is thought to suppress neuroblast growth via release of soluble differentiating factors. Here, we identified critical growth-limiting components of the differentiating stroma secretome and designed a potential therapeutic strategy based on their central mechanism of action. We demonstrated that expression of heparan sulfate proteoglycans (HSPGs), including TβRIII, GPC1, GPC3, SDC3, and SDC4, is low in neuroblasts and high in the Schwannian stroma. Evaluation of neuroblastoma patient microarray data revealed an association between TGFBR3, GPC1, and SDC3 expression and improved prognosis. Treatment of neuroblastoma cell lines with soluble HSPGs promoted neuroblast differentiation via FGFR1 and ERK phosphorylation, leading to upregulation of the transcription factor inhibitor of DNA binding 1 (ID1). HSPGs also enhanced FGF2-dependent differentiation, and the anticoagulant heparin had a similar effect, leading to decreased neuroblast proliferation. Dissection of individual sulfation sites identified 2-O, 3-O-desulfated heparin (ODSH) as a differentiating agent, and treatment of orthotopic xenograft models with ODSH suppressed tumor growth and metastasis without anticoagulation. These studies support heparan sulfate signaling intermediates as prognostic and therapeutic neuroblastoma biomarkers and demonstrate that tumor stroma biology can inform the design of targeted molecular therapeutics.

Authors
Knelson, EH; Gaviglio, AL; Nee, JC; Starr, MD; Nixon, AB; Marcus, SG; Blobe, GC
MLA Citation
Knelson, EH, Gaviglio, AL, Nee, JC, Starr, MD, Nixon, AB, Marcus, SG, and Blobe, GC. "Stromal heparan sulfate differentiates neuroblasts to suppress neuroblastoma growth." The Journal of clinical investigation 124.7 (July 2014): 3016-3031.
PMID
24937430
Source
epmc
Published In
Journal of Clinical Investigation
Volume
124
Issue
7
Publish Date
2014
Start Page
3016
End Page
3031
DOI
10.1172/jci74270

Modulation of circulating protein biomarkers following TRC105 (anti-endoglin antibody) treatment in patients with advanced cancer.

TRC105 is an endoglin-targeting drug that possesses anti-angiogenic and antitumor potential. Analysis of the initial phase I trial of TRC105 demonstrated good tolerability and efficacy in cancer patients. In this report, we analyzed multiple circulating biomarkers at baseline, cycle 2 day 1 (C2D1), and end of study (EOS) for each patient. The baseline level and the fold change from baseline to both C2D1 and EOS for each marker were statistically analyzed. At C2D1, seven markers were significantly downregulated (angiopoietin-2 [Ang-2], insulin-like growth factor-binding protein-3 [IGFBP-3], plasminogen activator inhibitor-1 [PAI-1] total, platelet-derived growth factor [PDGF]-AA, PDGF-BB, thrombospondin-1 [TSP-1], and vascular endothelial growth factor [VEGF]-D). Meanwhile, seven markers were upregulated by C2D1 (E-Cadherin, soluble Endoglin [sEnd], E-Selectin, interleukin-6 [IL-6], osteopontin [OPN], TSP-2, and von Willebrand factor [vWF]). At EOS, seven markers were upregulated including Ang-2, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), IGFBP-1, IL-6, TSP-2, and vascular cell adhesion molecule-1 (VCAM-1). A statistical trend was also seen for increases of VEGF-A and placenta growth factor (PlGF) at EOS. Throughout treatment, sEnd levels significantly increased, an observation that was recapitulated in cultured endothelial cells. This is the first report of plasma-based biomarkers in patients receiving TRC105. TRC105 treatment by C2D1 was associated with decreases in several angiogenic factors, including Ang-2, PDGF isoforms, and VEGF isoforms, offering insight into the mechanisms underlying TRC105's anti-angiogenic, antitumor function. Increases in sEnd were the most significant of all observed biomarker changes and may reflect direct drug effects. Additionally, biomarker changes in response to TRC105 are distinct from those seen in patients treated with VEGF-targeting drugs, suggesting the possible utility of combining these two classes of angiogenesis inhibitors in patients.

Authors
Liu, Y; Starr, MD; Brady, JC; Dellinger, A; Pang, H; Adams, B; Theuer, CP; Lee, NY; Hurwitz, HI; Nixon, AB
MLA Citation
Liu, Y, Starr, MD, Brady, JC, Dellinger, A, Pang, H, Adams, B, Theuer, CP, Lee, NY, Hurwitz, HI, and Nixon, AB. "Modulation of circulating protein biomarkers following TRC105 (anti-endoglin antibody) treatment in patients with advanced cancer." Cancer medicine 3.3 (June 2014): 580-591.
PMID
24574330
Source
epmc
Published In
Cancer Medicine
Volume
3
Issue
3
Publish Date
2014
Start Page
580
End Page
591
DOI
10.1002/cam4.207

The balance of cell surface and soluble type III TGF-β receptor regulates BMP signaling in normal and cancerous mammary epithelial cells.

Bone morphogenetic proteins (BMPs) are members of the TGF-β superfamily that are over-expressed in breast cancer, with context dependent effects on breast cancer pathogenesis. The type III TGF-β receptor (TβRIII) mediates BMP signaling. While TβRIII expression is lost during breast cancer progression, the role of TβRIII in regulating BMP signaling in normal mammary epithelium and breast cancer cells has not been examined. Restoring TβRIII expression in a 4T1 murine syngeneic model of breast cancer suppressed Smad1/5/8 phosphorylation and inhibited the expression of the BMP transcriptional targets, Id1 and Smad6, in vivo. Similarly, restoring TβRIII expression in human breast cancer cell lines or treatment with sTβRIII inhibited BMP-induced Smad1/5/8 phosphorylation and BMP-stimulated migration and invasion. In normal mammary epithelial cells, shRNA-mediated silencing of TβRIII, TβRIII over-expression, or treatment with sTβRIII inhibited BMP-mediated phosphorylation of Smad1/5/8 and BMP induced migration. Inhibition of TβRIII shedding through treatment with TAPI-2 or expression of a non-shedding TβRIII mutant rescued TβRIII mediated inhibition of BMP induced Smad1/5/8 phosphorylation and BMP induced migration and/or invasion in both in normal mammary epithelial cells and breast cancer cells. Conversely, expression of a TβRIII mutant, which exhibited increased shedding, significantly reduced BMP-mediated Smad1/5/8 phosphorylation, migration, and invasion. These data demonstrate that TβRIII regulates BMP-mediated signaling and biological effects, primarily through the ligand sequestration effects of sTβRIII in normal and cancerous mammary epithelial cells and suggest that the ratio of membrane bound versus sTβRIII plays an important role in mediating these effects.

Authors
Gatza, CE; Elderbroom, JL; Oh, SY; Starr, MD; Nixon, AB; Blobe, GC
MLA Citation
Gatza, CE, Elderbroom, JL, Oh, SY, Starr, MD, Nixon, AB, and Blobe, GC. "The balance of cell surface and soluble type III TGF-β receptor regulates BMP signaling in normal and cancerous mammary epithelial cells." Neoplasia (New York, N.Y.) 16.6 (June 2014): 489-500.
PMID
25077702
Source
epmc
Published In
Neoplasia (New York, N.Y.)
Volume
16
Issue
6
Publish Date
2014
Start Page
489
End Page
500
DOI
10.1016/j.neo.2014.05.008

Biomarker modulation in patients (pts) receiving TRC105 (T) and bevacizumab (B) in a phase Ib clinical trial.

Authors
Liu, Y; Clarke, JM; Starr, MD; Brady, JC; Pang, H; Rushing, C; Alvarez, D; Adams, BJ; Theuer, CP; Hurwitz, H; Nixon, AB
MLA Citation
Liu, Y, Clarke, JM, Starr, MD, Brady, JC, Pang, H, Rushing, C, Alvarez, D, Adams, BJ, Theuer, CP, Hurwitz, H, and Nixon, AB. "Biomarker modulation in patients (pts) receiving TRC105 (T) and bevacizumab (B) in a phase Ib clinical trial." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Prognostic and predictive tumor-based biomarkers in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (IFN) with or without bevacizumab (Bev): Results from CALGB (Alliance) 90206. 2

Authors
Kluger, HM; Halabi, S; Solomon, NC; Jilaveanu, L; Zito, C; Sznol, J; Nixon, AB; Rini, BI; Small, EJ; George, DJ
MLA Citation
Kluger, HM, Halabi, S, Solomon, NC, Jilaveanu, L, Zito, C, Sznol, J, Nixon, AB, Rini, BI, Small, EJ, and George, DJ. "Prognostic and predictive tumor-based biomarkers in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (IFN) with or without bevacizumab (Bev): Results from CALGB (Alliance) 90206. 2." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Prognostic and predictive blood-based biomarkers of overall survival (OS) in patients (pts) with advanced colorectal cancer (CRC) treated with cetuximab (C): Results from CALGB 80203 (Alliance).

Authors
Hatch, AJ; Pang, H; Starr, MD; Brady, JC; Jia, J; Jiang, C; Sibley, A; Owzar, K; Niedzwiecki, D; Venook, AP; Cushman, SM; Hurwitz, H; Nixon, AB
MLA Citation
Hatch, AJ, Pang, H, Starr, MD, Brady, JC, Jia, J, Jiang, C, Sibley, A, Owzar, K, Niedzwiecki, D, Venook, AP, Cushman, SM, Hurwitz, H, and Nixon, AB. "Prognostic and predictive blood-based biomarkers of overall survival (OS) in patients (pts) with advanced colorectal cancer (CRC) treated with cetuximab (C): Results from CALGB 80203 (Alliance)." May 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
15
Publish Date
2014

Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer.

PURPOSE: Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). METHODS: Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m(2) twice daily, days 1-14), oxaliplatin (130 mg/m(2) on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (src(act)) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). RESULTS: Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of src(act) expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src(act) expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). CONCLUSIONS: The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib.

Authors
Strickler, JH; McCall, S; Nixon, AB; Brady, JC; Pang, H; Rushing, C; Cohn, A; Starodub, A; Arrowood, C; Haley, S; Meadows, KL; Morse, MA; Uronis, HE; Blobe, GC; Hsu, SD; Zafar, SY; Hurwitz, HI
MLA Citation
Strickler, JH, McCall, S, Nixon, AB, Brady, JC, Pang, H, Rushing, C, Cohn, A, Starodub, A, Arrowood, C, Haley, S, Meadows, KL, Morse, MA, Uronis, HE, Blobe, GC, Hsu, SD, Zafar, SY, and Hurwitz, HI. "Phase I study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer." Invest New Drugs 32.2 (April 2014): 330-339.
PMID
24173967
Source
pubmed
Published In
Investigational New Drugs
Volume
32
Issue
2
Publish Date
2014
Start Page
330
End Page
339
DOI
10.1007/s10637-013-0042-9

Dasatinib (BMS-35482) interacts synergistically with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells with high SRC pathway activation and protein expression.

PURPOSE: This study aimed to explore the activity of dasatinib in combination with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells. METHODS: Cells with previously determined SRC pathway and protein expression (SRC pathway/SRC protein IGROV1, both high; SKOV3, both low) were treated with dasatinib in combination with the cytotoxic agents. SRC and paxillin protein expression were determined pretreatment and posttreatment. Dose-response curves were constructed, and the combination index (CI) for drug interaction was calculated. RESULTS: In the IGROV1 cells, dasatinib alone reduced phospho-SRC/total SRC 71% and p-paxillin/t-paxillin ratios 77%. Phospho-SRC (3%-33%; P = 0.002 to 0.04) and p-paxicillin (6%-19%; P = 0.01 to 0.05) levels were significantly reduced with dasatinib in combination with each cytotoxic agent. The combination of dasatinib and docetaxel, gemcitabine, or topotecan had a synergistic antiproliferative effect (CI, 0.49-0.68), whereas dasatinib combined with doxorubicin had an additive effect (CI, 1.08).In SKOV3 cells, dasatinib resulted in less pronounced reductions of phospho-SRC/total SRC (49%) and p-paxillin/t-paxillin (62%). Phospho-SRC (18%; P < 0.001) and p-paxillin levels (18%; P = 0.001; 9%; P = 0.007) were significantly decreased when dasatinib was combined with docetaxel and topotecan (p-paxillin only). Furthermore, dasatinib combined with the cytotoxics in the SKOV3 cells produced an antagonistic interaction on the proliferation of these cells (CI, 1.49-2.27). CONCLUSIONS: Dasatinib in combination with relapse chemotherapeutic agents seems to interact in a synergistic or additive manner in cells with high SRC pathway activation and protein expression. Further evaluation of dasatinib in combination with chemotherapy in ovarian cancer animal models and exploration of the use of biomarkers to direct therapy are warranted.

Authors
Secord, AA; Teoh, D; Jia, J; Nixon, AB; Grace, L; Adams, DJ; Murphy, SK
MLA Citation
Secord, AA, Teoh, D, Jia, J, Nixon, AB, Grace, L, Adams, DJ, and Murphy, SK. "Dasatinib (BMS-35482) interacts synergistically with docetaxel, gemcitabine, topotecan, and doxorubicin in ovarian cancer cells with high SRC pathway activation and protein expression." Int J Gynecol Cancer 24.2 (February 2014): 218-225.
PMID
24407585
Source
pubmed
Published In
International Journal of Gynecological Cancer
Volume
24
Issue
2
Publish Date
2014
Start Page
218
End Page
225
DOI
10.1097/IGC.0000000000000056

Prognostic and predictive blood-based biomarkers of overall survival (OS) in patients (pts) with advanced colorectal cancer (CRC) treated with cetuximab (C): Results from CALGB 80203 (Alliance)

Authors
Hatch, AJ; Pang, H; Starr, MD; Brady, JC; Jia, J; Niedzwiecki, D; Venook, AP; Cushman, SM; Hurwitz, H; Nixon, AB
MLA Citation
Hatch, AJ, Pang, H, Starr, MD, Brady, JC, Jia, J, Niedzwiecki, D, Venook, AP, Cushman, SM, Hurwitz, H, and Nixon, AB. "Prognostic and predictive blood-based biomarkers of overall survival (OS) in patients (pts) with advanced colorectal cancer (CRC) treated with cetuximab (C): Results from CALGB 80203 (Alliance)." January 20, 2014.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
32
Issue
3
Publish Date
2014

Phase i study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer

Purpose Dasatinib inhibits src family kinases and has anti-angiogenic properties. We conducted a phase I study of dasatinib, capecitabine, oxaliplatin, and bevacizumab (CapeOx/bevacizumab), with an expansion cohort in metastatic colorectal cancer (CRC). Methods Patients were enrolled in a dose escalation cohort to establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D). Using a "3 + 3" design, twelve patients with advanced solid tumors received dasatinib (50 mg twice daily or 70 mg daily), capecitabine (850 mg/m2 twice daily, days 1-14), oxaliplatin (130 mg/m2 on day 1) and bevacizumab (7.5 mg/kg on day1), every 3 weeks. Ten patients with previously untreated metastatic CRC were then enrolled in an expansion cohort. Activated src (srcact) expression was measured by immunohistochemistry, using an antibody that selectively recognizes the active conformation of src (clone 28). Results Twenty-two patients were enrolled between June 2009 and May 2011. Two DLTs were observed in the 50 mg bid dasatinib cohort, and one DLT was observed in the 70 mg daily dasatinib cohort. The MTD and RP2D for dasatinib was 70 mg daily. The most common treatment-related adverse events were fatigue (20; 91 %) and diarrhea (18; 82 %). Biomarker analysis of srcact expression demonstrated that the overall response rate (ORR) was 75 % (6/8) for patients with high src act expression (IHC ≥ 2), compared to 0 % (0/8) for patients with low srcact expression (IHC 0 or 1); (p = 0.007). Conclusions The RP2D of dasatinib is 70 mg daily in combination with CapeOx/bevacizumab. High levels of srcact expression may predict those patients most likely to benefit from dasatinib. © 2013 Springer Science+Business Media New York.

Authors
Strickler, JH; McCall, S; Nixon, AB; Brady, JC; Pang, H; Rushing, C; Cohn, A; Starodub, A; Arrowood, C; Haley, S; Meadows, KL; Morse, MA; Uronis, HE; Blobe, GC; Hsu, SD; Zafar, SY; Hurwitz, HI
MLA Citation
Strickler, JH, McCall, S, Nixon, AB, Brady, JC, Pang, H, Rushing, C, Cohn, A, Starodub, A, Arrowood, C, Haley, S, Meadows, KL, Morse, MA, Uronis, HE, Blobe, GC, Hsu, SD, Zafar, SY, and Hurwitz, HI. "Phase i study of dasatinib in combination with capecitabine, oxaliplatin and bevacizumab followed by an expanded cohort in previously untreated metastatic colorectal cancer." Investigational New Drugs 32.2 (January 1, 2014): 330-339.
Source
scopus
Published In
Investigational New Drugs
Volume
32
Issue
2
Publish Date
2014
Start Page
330
End Page
339
DOI
10.1007/s10637-013-0042-9

Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors

Purpose: To define maximum tolerated dose (MTD), toxicities, and pharmacodynamics of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumor patients. Design: This was a standard "3 + 3" dose-escalation trial. All subjects received bevacizumab 7.5 mg/kg on day 1 of each cycle. Doses for capecitabine, oxaliplatin and everolimus were modified per dose limiting toxicity (DLT). Baseline and on-treatment plasma biomarkers were analyzed. Archived tumor mRNA levels were evaluated for NRP1, NRP2 and VEGF-A isoforms. Results: Twenty-nine patients were evaluable for toxicity and 30 for efficacy. Two DLTs were observed in cohort 1 and one DLT each was observed in cohort -1 and -1b. Grade ≥3 toxicities included neutropenia, hypertension, perforation/fistula/hemorrhage, hypertriglyceridemia, diarrhea, and thromboembolism. Twelve subjects experienced partial response (PR); 12 had stable disease as best response. Three of seven chemorefractory metastatic colorectal cancer (mCRC) subjects experienced PR; 8 of 15 chemonaive mCRC subjects experienced PR. Plasma TβRIII and IL-6 increased on treatment but without correlation to outcome. Increased VEGF165 levels significantly correlated with longer progression free survival. Conclusions: Everolimus with full dose capecitabine, oxaliplatin, and bevacizumab had unacceptable toxicity. MTD was: everolimus 5 mg daily; capecitabine 680 mg/m2 BID days 1-14; oxaliplatin 100 mg/m2 and bevacizumab 7.5 mg/kg, day 1. Activity was noted in mCRC. © 2014 Springer Science+Business Media.

Authors
Rangwala, F; Bendell, JC; Kozloff, MF; Arrowood, CC; Dellinger, A; Meadows, J; Tourt-Uhlig, S; Murphy, J; Meadows, KL; Starr, A; Broderick, S; Brady, JC; Cushman, SM; Morse, MA; Uronis, HE; Hsu, SD; Zafar, SY; Wallace, J; Starodub, AN; Strickler, JH; Pang, H; Nixon, AB; Hurwitz, HI
MLA Citation
Rangwala, F, Bendell, JC, Kozloff, MF, Arrowood, CC, Dellinger, A, Meadows, J, Tourt-Uhlig, S, Murphy, J, Meadows, KL, Starr, A, Broderick, S, Brady, JC, Cushman, SM, Morse, MA, Uronis, HE, Hsu, SD, Zafar, SY, Wallace, J, Starodub, AN, Strickler, JH, Pang, H, Nixon, AB, and Hurwitz, HI. "Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors." Investigational New Drugs 32.4 (January 1, 2014): 700-709.
Source
scopus
Published In
Investigational New Drugs
Volume
32
Issue
4
Publish Date
2014
Start Page
700
End Page
709
DOI
10.1007/s10637-014-0089-2

A phase Ib study of combined VEGFR and mTOR inhibition with Vatalanib and everolimus in patients with advanced renal cell carcinoma

Background Vatalanib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), whereas everolimus inhibits mammalian target of rapamycin (mTOR). Combination therapy with VEGFR and mTOR inhibitors has not been well tolerated to date but may have efficacy in renal cell carcinoma (RCC). Patients and Methods A phase Ib study of vatalanib and everolimus was performed in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), safety, and tolerability of the combination. A dose-expansion cohort of 20 patients with metastatic RCC was studied to further define toxicity and preliminary efficacy in patients with RCC. Results We evaluated 32 patients over 3 dose levels and a dose-expansion cohort. The most common toxicities of any grade were proteinuria, fatigue, hypertriglyceridemia, nausea, and vomiting. Dose-limiting toxicities (DLTs) included severe hypertension, diarrhea, neutropenia, mucositis, and fatigue. The MTD for the combination was vatalanib 1000 mg daily and everolimus 5 mg daily. In all patients, median overall survival (OS) was 16.3 months. In patients with RCC, median progression-free survival (PFS) was 5.8 months, and OS was 16.5 months. OS was significantly better in treatment-naive patients (25.1 months) compared with patients who had received previous vascular endothelial growth factor (VEGF)-targeted therapy (6.3 months). Seven of 24 (29.2%) evaluable patients demonstrated a partial response, and an additional 15 patients exhibited stable disease. Long-term tolerability (> 1 year) was demonstrated in 19% of patients. Conclusion Relevant doses of vatalanib and everolimus were achieved in combination, with expected toxicities. A substantial number of patients with RCC achieved an objective response in the treatment-naive setting, with prolonged tolerability and survival. Further comparative phase II/III studies of specifically targeted VEGF and mTOR inhibitor combinations may be warranted in patients with RCC. © 2014 Elsevier Inc. All rights reserved.

Authors
Bitting, RL; Healy, P; Creel, PA; Turnbull, J; Morris, K; Wood, SY; Hurwitz, HI; Starr, MD; Nixon, AB; Armstrong, AJ; George, DJ
MLA Citation
Bitting, RL, Healy, P, Creel, PA, Turnbull, J, Morris, K, Wood, SY, Hurwitz, HI, Starr, MD, Nixon, AB, Armstrong, AJ, and George, DJ. "A phase Ib study of combined VEGFR and mTOR inhibition with Vatalanib and everolimus in patients with advanced renal cell carcinoma." Clinical Genitourinary Cancer 12.4 (January 1, 2014): 241-250.
Source
scopus
Published In
Clinical genitourinary cancer
Volume
12
Issue
4
Publish Date
2014
Start Page
241
End Page
250
DOI
10.1016/j.clgc.2013.11.020

Integrative Pathway Analysis Using Graph-Based Learning with Applications to TCGA Colon and Ovarian Data.

Recent method development has included multi-dimensional genomic data algorithms because such methods have more accurately predicted clinical phenotypes related to disease. This study is the first to conduct an integrative genomic pathway-based analysis with a graph-based learning algorithm. The methodology of this analysis, graph-based semi-supervised learning, detects pathways that improve prediction of a dichotomous variable, which in this study is cancer stage. This analysis integrates genome-level gene expression, methylation, and single nucleotide polymorphism (SNP) data in serous cystadenocarcinoma (OV) and colon adenocarcinoma (COAD). The top 10 ranked predictive pathways in COAD and OV were biologically relevant to their respective cancer stages and significantly enhanced prediction accuracy and area under the ROC curve (AUC) when compared to single data-type analyses. This method is an effective way to simultaneously predict binary clinical phenotypes and discover their biological mechanisms.

Authors
Dellinger, AE; Nixon, AB; Pang, H
MLA Citation
Dellinger, AE, Nixon, AB, and Pang, H. "Integrative Pathway Analysis Using Graph-Based Learning with Applications to TCGA Colon and Ovarian Data." Cancer informatics 13.Suppl 4 (January 2014): 1-9.
PMID
25125969
Source
epmc
Published In
Cancer Informatics
Volume
13
Issue
Suppl 4
Publish Date
2014
Start Page
1
End Page
9
DOI
10.4137/cin.s13634

Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines.

To explore the activity of dasatinib alone and in combination with gemcitabine and docetaxel in uterine leiomyosarcoma (uLMS) cell lines, and determine if dasatinib inhibits the SRC pathway.SK-UT-1 and SK-UT-1B uLMS cells were treated with gemcitabine, docetaxel and dasatinib individually and in combination. SRC and paxcillin protein expression were determined pre- and post-dasatinib treatment using Meso Scale Discovery (MSD) multi-array immunogenicity assay. Dose-response curves were constructed and the coefficient of drug interaction (CDI) and combination index (CI) for drug interaction calculated.Activated phosphorylated levels of SRC and paxillin were decreased after treatment with dasatinib in both cell lines (p < 0.001). The addition of a minimally active concentration of dasatinib (IC25) decreased the IC50 of each cytotoxic agent by 2-4 fold. The combination of gemcitabine-docetaxel yielded a synergistic effect in SK-UT-1 (CI = 0.59) and an antagonistic effect in SK-UT-1B (CI = 1.36). Dasatinib combined with gemcitabine or docetaxel revealed a synergistic anti-tumor effect (CDI < 1) in both cell lines. The triple drug combination and sequencing revealed conflicting results with a synergistic effect in SK-UT-1B and antagonistic in SK-UT-1.Dasatinib inhibits the SRC pathway and yields a synergistic effect with the two-drug combination with either gemcitabine or docetaxel. The value of adding dasatinib to gemcitabine and docetaxel in a triple drug combination is uncertain, but may be beneficial in select uLMS cell lines. Based on our pre-clinical data and known activity of gemcitabine and docetaxel, further evaluation of dasatinib in combination with these agents for the treatment of uLMS is warranted.

Authors
Lopez-Acevedo, M; Grace, L; Teoh, D; Whitaker, R; Adams, DJ; Jia, J; Nixon, AB; Secord, AA
MLA Citation
Lopez-Acevedo, M, Grace, L, Teoh, D, Whitaker, R, Adams, DJ, Jia, J, Nixon, AB, and Secord, AA. "Dasatinib (BMS-35482) potentiates the activity of gemcitabine and docetaxel in uterine leiomyosarcoma cell lines." Gynecologic oncology research and practice 1 (January 2014): 2-.
Website
http://hdl.handle.net/10161/12496
PMID
27231555
Source
epmc
Published In
Gynecologic Oncology Research and Practice
Volume
1
Publish Date
2014
Start Page
2
DOI
10.1186/2053-6844-1-2

Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling

Endoglin is a transforming growth factor β (TGF-β) coreceptor that serves as a prognostic, diagnostic and therapeutic vascular target in human cancer. A number of endoglin ectodomain-targeting antibodies (Abs) can effectively suppress both normal and tumor-associated angiogenesis, but their molecular actions remain poorly characterized. Here we define a key mechanism for TRACON105 (TRC105), a humanized monoclonal Ab in clinical trials for treatment of advanced or metastatic tumors. TRC105, along with several other endoglin Abs tested, enhance endoglin shedding through direct coupling of endoglin and the membrane-type 1 matrix metalloproteinase (MMP)-14 at the cell surface to release the antiangiogenic factor, soluble endoglin (sEng). In addition to this coupling process, endoglin shedding is further amplified by increased MMP-14 expression that requires TRC105 concentration-dependent c-Jun N-terminal kinase (JNK) activation. There were also notable counterbalancing effects on canonical Smad signaling in which TRC105 abrogated both the steady-state and TGF-β-induced Smad1/5/8 activation while augmenting Smad2/3 activation. Interestingly, TRC105-induced sEng and aberrant Smad signaling resulted in an excessive migratory response through enhanced stress fiber formation and disruption of endothelial cell-cell junctions. Collectively, our study defines endoglin shedding and deregulated TGF-β signaling during migration as major mechanisms by which TRC105 inhibits angiogenesis. © 2014 Macmillan Publishers Limited.

Authors
Kumar, S; Pan, CC; Bloodworth, JC; Nixon, AB; Theuer, C; Hoyt, DG; Lee, NY
MLA Citation
Kumar, S, Pan, CC, Bloodworth, JC, Nixon, AB, Theuer, C, Hoyt, DG, and Lee, NY. "Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling." Oncogene 33.30 (2014): 3970-3979.
Source
scival
Published In
Oncogene: Including Oncogene Reviews
Volume
33
Issue
30
Publish Date
2014
Start Page
3970
End Page
3979
DOI
10.1038/onc.2013.386

Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance).

PURPOSE: CALGB80303 was a phase III trial of 602 patients with locally advanced or metastatic pancreatic cancer comparing gemcitabine/bevacizumab versus gemcitabine/placebo. The study found no benefit in any outcome from the addition of bevacizumab to gemcitabine. Blood samples were collected and multiple angiogenic factors were evaluated and then correlated with clinical outcome in general (prognostic markers) and with benefit specifically from bevacizumab treatment (predictive markers). EXPERIMENTAL DESIGN: Plasma samples were analyzed via a novel multiplex ELISA platform for 31 factors related to tumor growth, angiogenesis, and inflammation. Baseline values for these factors were correlated with overall survival (OS) using univariate Cox proportional hazard regression models and multivariable Cox regression models with leave-one-out cross validation. Predictive markers were identified using a treatment by marker interaction term in the Cox model. RESULTS: Baseline plasma was available from 328 patients. Univariate prognostic markers for OS were identified including: Ang2, CRP, ICAM-1, IGFBP-1, TSP-2 (all P < 0.001). These prognostic factors were found to be highly significant, even after adjustment for known clinical factors. Additional modeling approaches yielded prognostic signatures from multivariable Cox regression. The gemcitabine/bevacizumab signature consisted of IGFBP-1, interleukin-6, PDGF-AA, PDGF-BB, TSP-2; whereas the gemcitabine/placebo signature consisted of CRP, IGFBP-1, PAI-1, PDGF-AA, P-selectin (both P < 0.0001). Finally, three potential predictive markers of bevacizumab efficacy were identified: VEGF-D (P < 0.01), SDF1 (P < 0.05), and Ang2 (P < 0.05). CONCLUSION: This study identified strong prognostic markers for pancreatic cancer patients. Predictive marker analysis indicated that plasma levels of VEGF-D, Ang2, and SDF1 significantly predicted for benefit or lack of benefit from bevacizumab in this population.

Authors
Nixon, AB; Pang, H; Starr, MD; Friedman, PN; Bertagnolli, MM; Kindler, HL; Goldberg, RM; Venook, AP; Hurwitz, HI; Alliance for Clinical Trials In Oncology,
MLA Citation
Nixon, AB, Pang, H, Starr, MD, Friedman, PN, Bertagnolli, MM, Kindler, HL, Goldberg, RM, Venook, AP, Hurwitz, HI, and Alliance for Clinical Trials In Oncology, . "Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: results from CALGB80303 (Alliance)." Clin Cancer Res 19.24 (December 15, 2013): 6957-6966.
PMID
24097873
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
19
Issue
24
Publish Date
2013
Start Page
6957
End Page
6966
DOI
10.1158/1078-0432.CCR-13-0926

Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.

Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-β receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-β signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-β inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment.

Authors
Hanks, BA; Holtzhausen, A; Evans, KS; Jamieson, R; Gimpel, P; Campbell, OM; Hector-Greene, M; Sun, L; Tewari, A; George, A; Starr, M; Nixon, A; Augustine, C; Beasley, G; Tyler, DS; Osada, T; Morse, MA; Ling, L; Lyerly, HK; Blobe, GC
MLA Citation
Hanks, BA, Holtzhausen, A, Evans, KS, Jamieson, R, Gimpel, P, Campbell, OM, Hector-Greene, M, Sun, L, Tewari, A, George, A, Starr, M, Nixon, A, Augustine, C, Beasley, G, Tyler, DS, Osada, T, Morse, MA, Ling, L, Lyerly, HK, and Blobe, GC. "Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment." J Clin Invest 123.9 (September 2013): 3925-3940.
Website
http://hdl.handle.net/10161/13297
PMID
23925295
Source
pubmed
Published In
Journal of Clinical Investigation
Volume
123
Issue
9
Publish Date
2013
Start Page
3925
End Page
3940
DOI
10.1172/JCI65745

A phase I study of ABT-510 plus bevacizumab in advanced solid tumors.

Targeting multiple regulators of tumor angiogenesis have the potential to improve treatment efficacy. Bevacizumab is a monoclonal antibody directed against vascular endothelial growth factor and ABT-510 is a synthetic analog of thrombospondin, an endogenous angiogenesis inhibitor. Dual inhibition may result in additional benefit. We evaluated the safety, tolerability, and efficacy of the combination of bevacizumab plus ABT-510 in patients with refractory solid tumors. We also explored the effects of these agents on plasma-based biomarkers and wound angiogenesis. Thirty-four evaluable subjects were enrolled and received study drug. Therapy was well tolerated; minimal treatment-related grade 3/4 toxicity was observed. One patient treated at dose level 1 had a partial response and five other patients treated at the recommended phase II dose had prolonged stable disease for more than 1 year. Biomarker evaluation revealed increased levels of D-dimer, von Willebrand factor, placental growth factor, and stromal-derived factor 1 in response to treatment with the combination of bevacizumab and ABT-510. Data suggest that continued evaluation of combination antiangiogenesis therapies may be clinically useful.

Authors
Uronis, HE; Cushman, SM; Bendell, JC; Blobe, GC; Morse, MA; Nixon, AB; Dellinger, A; Starr, MD; Li, H; Meadows, K; Gockerman, J; Pang, H; Hurwitz, HI
MLA Citation
Uronis, HE, Cushman, SM, Bendell, JC, Blobe, GC, Morse, MA, Nixon, AB, Dellinger, A, Starr, MD, Li, H, Meadows, K, Gockerman, J, Pang, H, and Hurwitz, HI. "A phase I study of ABT-510 plus bevacizumab in advanced solid tumors." Cancer Med 2.3 (June 2013): 316-324.
Website
http://hdl.handle.net/10161/11086
PMID
23930208
Source
pubmed
Published In
Cancer Medicine
Volume
2
Issue
3
Publish Date
2013
Start Page
316
End Page
324
DOI
10.1002/cam4.65

Identification of predictive biomarkers of overall survival (OS) in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (I) with or without bevacizumab (B): Results from CALGB 90206 (Alliance)

Authors
Nixon, AB; Halabi, S; Shterev, I; Starr, M; Brady, JC; Dutcher, JP; Hopkins, JO; Hurwitz, H; Small, EJ; Rini, BI; Febbo, PG; George, DJ; Oncology, ACT
MLA Citation
Nixon, AB, Halabi, S, Shterev, I, Starr, M, Brady, JC, Dutcher, JP, Hopkins, JO, Hurwitz, H, Small, EJ, Rini, BI, Febbo, PG, George, DJ, and Oncology, ACT. "Identification of predictive biomarkers of overall survival (OS) in patients (pts) with advanced renal cell carcinoma (RCC) treated with interferon alpha (I) with or without bevacizumab (B): Results from CALGB 90206 (Alliance)." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Circulating cytokines and angiogenic factors (CAF) as markers of clinical response in the study of trametinib (T) plus gemcitabine (G) versus placebo (P) plus gemcitabine for patients (pts) with untreated metastatic adenocarcinoma of the pancreas (MEK113487)

Authors
Heymach, J; Tran, HT; Nixon, AB; Hurwitz, H; Infante, JR; Gagnon, RC; Steplewski, K; Le, NT; Liu, Y
MLA Citation
Heymach, J, Tran, HT, Nixon, AB, Hurwitz, H, Infante, JR, Gagnon, RC, Steplewski, K, Le, NT, and Liu, Y. "Circulating cytokines and angiogenic factors (CAF) as markers of clinical response in the study of trametinib (T) plus gemcitabine (G) versus placebo (P) plus gemcitabine for patients (pts) with untreated metastatic adenocarcinoma of the pancreas (MEK113487)." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Tumor markers of efficacy and resistance to cetuximab (C) treatment in metastatic colorectal cancer (mCRC): Results from CALGB 80203 (Alliance)

Authors
Hurwitz, H; Cushman, S; Jiang, C; Shterev, I; Mahoney, MR; Niedzwiecki, D; Mayer, RJ; Venook, AP; Owzar, K; Nixon, AB; Oncology, ACT
MLA Citation
Hurwitz, H, Cushman, S, Jiang, C, Shterev, I, Mahoney, MR, Niedzwiecki, D, Mayer, RJ, Venook, AP, Owzar, K, Nixon, AB, and Oncology, ACT. "Tumor markers of efficacy and resistance to cetuximab (C) treatment in metastatic colorectal cancer (mCRC): Results from CALGB 80203 (Alliance)." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Correlation of Src activation with response to dasatinib, capecitabine, oxaliplatin, and bevacizumab in advanced solid tumors

Authors
Strickler, JH; McCall, S; Nixon, AB; Pang, H; Rushing, C; Arrowood, C; Haley, S; Meadows, K; Hurwitz, H
MLA Citation
Strickler, JH, McCall, S, Nixon, AB, Pang, H, Rushing, C, Arrowood, C, Haley, S, Meadows, K, and Hurwitz, H. "Correlation of Src activation with response to dasatinib, capecitabine, oxaliplatin, and bevacizumab in advanced solid tumors." May 20, 2013.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
31
Issue
15
Publish Date
2013

Abstract 5041: The type III TGF-beta receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma.

Authors
Knelson, EH; Gaviglio, AL; Tewari, AK; Armstrong, MB; Nixon, AB; Starr, MD; Mythreye, K; Blobe, GC
MLA Citation
Knelson, EH, Gaviglio, AL, Tewari, AK, Armstrong, MB, Nixon, AB, Starr, MD, Mythreye, K, and Blobe, GC. "Abstract 5041: The type III TGF-beta receptor promotes FGF2-mediated neuronal differentiation in neuroblastoma." April 15, 2013.
Source
crossref
Published In
Cancer Research
Volume
73
Issue
8 Supplement
Publish Date
2013
Start Page
5041
End Page
5041
DOI
10.1158/1538-7445.AM2013-5041

Correlation of angiogenic biomarker signatures with clinical outcomes in metastatic colorectal cancer patients receiving capecitabine, oxaliplatin, and bevacizumab.

A novel combination of capecitabine, oxaliplatin, and bevacizumab was evaluated in colorectal cancer patients enrolled in a phase II clinical trial. In this retrospective analysis, plasma samples from patients receiving capecitabine, oxaliplatin, and bevacizumab were analyzed to investigate biomarkers of clinical benefit. Forty-one protein biomarkers were tested in 38 patients at baseline and after two cycles of drug administration. Correlations among analytes were evaluated by Spearman analysis. Analyte levels at baseline and changes on-treatment were correlated with progression-free survival (PFS) and overall survival (OS) by univariate analysis. Multivariate analyses were determined using the Cox proportional hazard model. Time to event analyses were evaluated by Kaplan-Meier analysis and compared by log-rank test. Baseline levels of vWF and Ang-2 significantly correlated with PFS, while levels of VCAM-1, vWF, TSP-2, IL-8, MMP-2, and Ang-2 correlated with OS (P < 0.05). The fold change of IGF-1 levels from baseline to the end of cycle 2 was correlated with PFS, while fold changes of Ang-2, TSP-2, and TGF-β2 correlated with OS. A baseline signature of Ang-2, IGFBP-3, IL-6, and VCAM-1 identified a low-risk and high-risk group of patients (OS: 33.9 months vs. 18.1 months, respectively, P = 0.016). For treatment-related changes, a signature consisting of Ang-2, E-Cadherin, IL-6, MCP-1, OPN, and TGF-β1 was able to stratify patients into high- and low-risk groups (PFS: 7.7 months vs. 15.5 months, P = 0.004). Multiplex analysis of patient plasma in this trial identified several baseline- and treatment-related biomarkers associated with clinical outcome. These findings merit further exploration in larger, controlled clinical trials.

Authors
Liu, Y; Starr, MD; Bulusu, A; Pang, H; Wong, NS; Honeycutt, W; Amara, A; Hurwitz, HI; Nixon, AB
MLA Citation
Liu, Y, Starr, MD, Bulusu, A, Pang, H, Wong, NS, Honeycutt, W, Amara, A, Hurwitz, HI, and Nixon, AB. "Correlation of angiogenic biomarker signatures with clinical outcomes in metastatic colorectal cancer patients receiving capecitabine, oxaliplatin, and bevacizumab." Cancer Med 2.2 (April 2013): 234-242.
PMID
23634291
Source
pubmed
Published In
Cancer Med
Volume
2
Issue
2
Publish Date
2013
Start Page
234
End Page
242
DOI
10.1002/cam4.71

Dual inhibition of αV integrins and Src kinase activity as a combination therapy strategy for colorectal cancer.

Both Src and αV integrins are important for tumor growth and angiogenesis. They are interconnected and responsible for important features of the tumor phenotype including invasiveness, metastasis, angiogenesis, and resistance to apoptosis. This study examines whether combinational inhibition of both integrin and Src pathways would exert greater antiangiogenesis and antitumor effects than either pathway alone. Using in-vitro cell culture systems, the activity of CNTO95 (Intetumumab), an αV integrin inhibitor, and dasatinib, an Src inhibitor, on proliferation, adhesion, and migration was evaluated in colon cancer cell lines, HCT-116 and RKO, as well as HUVEC cells. The antiangiogenic effect of this combinatory regimen was also tested using an in-vitro tubular network formation assay. The effects of CNTO95 and dasatinib on the activation of Src and integrin pathway signal transduction were also determined by western blotting. The combination of CNTO95 plus dasatinib inhibited adhesion, migration, and paxillin phosphorylation in both HCT-116 and RKO cells. CNTO95 and dasatinib also led to increased apoptosis of HCT-116 cells; however, similar effects were not observed in RKO cells. In addition, dual treatment of CNTO95 and dasatinib exerted enhanced effects on HUVEC cell proliferation, invasion, tubular network formation, and paxillin phosphorylation. In conclusion, our results suggest that concurrent inhibition of both the integrin and the Src pathways exert more pronounced antiangiogenic and antitumor effects than with either pathway being inhibited alone.

Authors
Jia, J; Starodub, A; Cushman, I; Liu, Y; Marshall, DJ; Hurwitz, HI; Nixon, AB
MLA Citation
Jia, J, Starodub, A, Cushman, I, Liu, Y, Marshall, DJ, Hurwitz, HI, and Nixon, AB. "Dual inhibition of αV integrins and Src kinase activity as a combination therapy strategy for colorectal cancer." Anticancer Drugs 24.3 (March 2013): 237-250.
PMID
23275294
Source
pubmed
Published In
Anti-Cancer Drugs
Volume
24
Issue
3
Publish Date
2013
Start Page
237
End Page
250
DOI
10.1097/CAD.0b013e32835d29fd

Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling

Endoglin is a transforming growth factor β (TGF-β) coreceptor that serves as a prognostic, diagnostic and therapeutic vascular target in human cancer. A number of endoglin ectodomain-targeting antibodies (Abs) can effectively suppress both normal and tumor-associated angiogenesis, but their molecular actions remain poorly characterized. Here we define a key mechanism for TRACON105 (TRC105), a humanized monoclonal Ab in clinical trials for treatment of advanced or metastatic tumors. TRC105, along with several other endoglin Abs tested, enhance endoglin shedding through direct coupling of endoglin and the membrane-type 1 matrix metalloproteinase (MMP)-14 at the cell surface to release the antiangiogenic factor, soluble endoglin (sEng). In addition to this coupling process, endoglin shedding is further amplified by increased MMP-14 expression that requires TRC105 concentration-dependent c-Jun N-terminal kinase (JNK) activation. There were also notable counterbalancing effects on canonical Smad signaling in which TRC105 abrogated both the steady-state and TGF-β-induced Smad1/5/8 activation while augmenting Smad2/3 activation. Interestingly, TRC105-induced sEng and aberrant Smad signaling resulted in an excessive migratory response through enhanced stress fiber formation and disruption of endothelial cell-cell junctions. Collectively, our study defines endoglin shedding and deregulated TGF-β signaling during migration as major mechanisms by which TRC105 inhibits angiogenesis.Oncogene advance online publication, 30 September 2013; doi:10.1038/onc.2013.386.

Authors
Kumar, S; Pan, CC; Bloodworth, JC; Nixon, A; Theuer, C; Hoyt, DG; Lee, NY
MLA Citation
Kumar, S, Pan, CC, Bloodworth, JC, Nixon, A, Theuer, C, Hoyt, DG, and Lee, NY. "Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling." Oncogene (2013).
PMID
24077288
Source
scival
Published In
Oncogene: Including Oncogene Reviews
Publish Date
2013
DOI
10.1038/onc.2013.386

A phase II study of capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas.

BACKGROUND: Esophageal and gastric cancers often present at an advanced stage. Systemic chemotherapy is the mainstay of treatment, but survival with current regimens remains poor. We evaluated the safety, tolerability, and efficacy of the combination capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas. METHODS: Thirty-seven patients with metastatic or unresectable gastric/gastroesophageal junction tumors were enrolled and treated with capecitabine 850 mg/m(2) BID on days 1-14, and oxaliplatin 130 mg/m(2) with bevacizumab 15 mg/kg on day 1 of a 21-day cycle. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate (RR) and overall survival (OS). Neuropilin-1 (NRP1) and -2 (NRP2) mRNA expression was evaluated in archived tumor. RESULTS: Thirty-five patients were evaluable for efficacy. Median PFS was 7.2 months; median OS was 10.8 months. RR was estimated at 51.4%. The regimen was tolerable with expected drug class-related toxicities. NRP2 mRNA levels significantly correlated with PFS (p = 0.042) and showed a trend toward significance with OS (p = 0.051). Nonsignificant trends for NRP1 were noted for higher expression levels and worse outcome. CONCLUSIONS: Bevacizumab can be given safely with chemotherapy in patients with metastatic esophagogastric adenocarcinomas. The combination of capecitabine, oxaliplatin, plus bevacizumab has activity comparable to other bevacizumab-containing regimens in metastatic gastroesophageal cancer.

Authors
Uronis, HE; Bendell, JC; Altomare, I; Blobe, GC; Hsu, SD; Morse, MA; Pang, H; Zafar, SY; Conkling, P; Favaro, J; Arrowood, CC; Cushman, SM; Meadows, KL; Brady, JC; Nixon, AB; Hurwitz, HI
MLA Citation
Uronis, HE, Bendell, JC, Altomare, I, Blobe, GC, Hsu, SD, Morse, MA, Pang, H, Zafar, SY, Conkling, P, Favaro, J, Arrowood, CC, Cushman, SM, Meadows, KL, Brady, JC, Nixon, AB, and Hurwitz, HI. "A phase II study of capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas." Oncologist 18.3 (2013): 271-272.
PMID
23485624
Source
pubmed
Published In
The oncologist
Volume
18
Issue
3
Publish Date
2013
Start Page
271
End Page
272
DOI
10.1634/theoncologist.2012-0404

Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors.

PURPOSE: To define the maximum tolerated dose, clinical toxicities, and pharmacodynamics of bevacizumab, everolimus, and panobinostat (LBH-589) when administered in combination to patients with advanced solid tumor malignancies. EXPERIMENT DESIGN: Subjects received 10 mg of panobinostat three times weekly, 5 or 10 mg everolimus daily, and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Protein acetylation was assessed in peripheral blood mononuclear cells (PBMC) both at baseline and on treatment. RESULTS: Twelve subjects were evaluable for toxicity and nine subjects for response. DLTs in cohort 1 included grade 2 esophagitis and grade 3 oral mucositis; DLTs in cohort -1 were grade 2 ventricular arrhythmia and grade 2 intolerable skin rash. Common adverse events were diarrhea (50 %), headache (33 %), mucositis/stomatitis (25 %), hyperlipidemia (25 %), and thrombocytopenia (25 %). There was 1 partial response; an additional 2 subjects had stable disease as best response. No consistent changes in protein acetylation in PBMC were observed in samples available from eight patients on treatment compared with baseline. CONCLUSIONS: Bevacizumab, everolimus, and panobinostat in combination at the lowest proposed doses did not have an acceptable safety and tolerability profile and did not consistently inhibit HDAC activity; therefore, we do not recommend further evaluation.

Authors
Strickler, JH; Starodub, AN; Jia, J; Meadows, KL; Nixon, AB; Dellinger, A; Morse, MA; Uronis, HE; Marcom, PK; Zafar, SY; Haley, ST; Hurwitz, HI
MLA Citation
Strickler, JH, Starodub, AN, Jia, J, Meadows, KL, Nixon, AB, Dellinger, A, Morse, MA, Uronis, HE, Marcom, PK, Zafar, SY, Haley, ST, and Hurwitz, HI. "Phase I study of bevacizumab, everolimus, and panobinostat (LBH-589) in advanced solid tumors." Cancer Chemother Pharmacol 70.2 (August 2012): 251-258.
PMID
22744359
Source
pubmed
Published In
Cancer Chemotherapy and Pharmacology
Volume
70
Issue
2
Publish Date
2012
Start Page
251
End Page
258
DOI
10.1007/s00280-012-1911-1

Modulation of pharmacodynamic (PD) biomarkers in dermal biopsies from patients treated on a phase I study of bevacizumab (Bev) in combination with everolimus (Ev) and erlotinib (Erl) for advanced solid tumors

Authors
Jia, J; Li, H; Dellinger, A; Pang, H; Russell, KB; Hurwitz, H; Nixon, AB
MLA Citation
Jia, J, Li, H, Dellinger, A, Pang, H, Russell, KB, Hurwitz, H, and Nixon, AB. "Modulation of pharmacodynamic (PD) biomarkers in dermal biopsies from patients treated on a phase I study of bevacizumab (Bev) in combination with everolimus (Ev) and erlotinib (Erl) for advanced solid tumors." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Modulation of angiogenic biomarkers in patients receiving high-dose TRC105

Authors
Liu, Y; Starr, M; Brady, JC; Pang, H; Dellinger, A; Leigh, BR; Theuer, CP; Hurwitz, H; Nixon, AB
MLA Citation
Liu, Y, Starr, M, Brady, JC, Pang, H, Dellinger, A, Leigh, BR, Theuer, CP, Hurwitz, H, and Nixon, AB. "Modulation of angiogenic biomarkers in patients receiving high-dose TRC105." May 20, 2012.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
30
Issue
15
Publish Date
2012

Modulation of angiogenic biomarkers in patients treated on a phase I study of TRC105 (anti-CD105 antibody) monotherapy for advanced solid tumors.

10565 Background: CD105 (endoglin) is an important mediator of tumor angiogenesis that is upregulated by hypoxia and VEGF inhibitors. TRC105 is an anti-CD105 monoclonal antibody currently being evaluated in clinical trials as an anti-angiogenic cancer therapy.In this first-in-human phase I study, pts with advanced, incurable solid tumors were treated with escalating doses of TRC105, iv every 2 wks, until disease progression. Serial plasma samples were analyzed via a novel multiplex ELISA platform optimized for cancer patients. 39 candidate biomarkers related to tumor growth, angiogenesis, and inflammation were assayed at baseline (BL), after 1 month, and at end of study (EOS).19 pts treated with TRC105 at 0.01-1 mg/kg were evaluable for biomarker analysis. Spearman's rank correlation coefficients were calculated for pairs of analytes with known interactions. Wilcoxon signed rank tests indicated that the following analytes were significantly down-regulated at one month when compared with baseline: IGFBP-3 (p=0.001), VEGF-C (p=0.002), VEGF-D (p=0.003), FGFb (p=0.008), PDGF-AA (p=0.011), PDGF-BB (p=0.039), and PIGF (p=0.045). By EOS, significant increases from the 1 month nadir were observed for the following analytes: VEGF-C (p=0.027), VEGF-D (p=0.034), and IGFBP-3 (p=0.043).This is the first systematic investigation of the effect(s) of TRC105 on angiogenic biomarkers in the clinical setting. Multiplex analyses indicate that TRC105 therapy is associated with down-regulation of key modulators of angiogenesis that later increase at the time of disease progression. Based on these preliminary findings, additional analyses are planned for pts treated at higher TRC105 doses as well as pts treated on phase Ib and phase II studies of TRC105 in combination with VEGF inhibitors and other standard-of-care cancer therapies.

Authors
Liu, Y; Starr, M; Pang, H; Marcello, J; Leigh, BR; Theuer, CP; Hurwitz, H; Nixon, AB
MLA Citation
Liu, Y, Starr, M, Pang, H, Marcello, J, Leigh, BR, Theuer, CP, Hurwitz, H, and Nixon, AB. "Modulation of angiogenic biomarkers in patients treated on a phase I study of TRC105 (anti-CD105 antibody) monotherapy for advanced solid tumors." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 10565-.
PMID
28021897
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
10565

Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: Results from CALGB 80303.

10508 Background: CALGB 80303 was a phase III trial of 602 patients (pts) with locally advanced or metastatic pancreatic cancer (PC) comparing gemcitabine + bevacizumab (GB) vs. gemcitabine + placebo (GP). That study found no overall survival (OS) benefit from the addition of B. Blood samples were collected for prospective biomarker analyses.Plasma samples were analyzed via a novel multiplex ELISA platform for >40 candidate factors related to tumor growth, angiogenesis, and inflammation. This platform was optimized for use in cancer patients. Baseline values were correlated with OS using univariate Cox proportional hazard regression models and multivariate Cox models with leave-one-out cross validation (LOOCV). Potential predictive markers were identified using a treatment by marker interaction term in the Cox model.328 pts had baseline samples available. Univariate prognostic markers predicting OS identified within the GB and GP cohorts included: Ang2, CRP, ICAM-1, IGFBP-1, TSP-2 (all p<0.001). By multivariate analysis, these markers were significantly more prognostic than standard clinical factors, such as age, gender, extent of disease and performance status. LOOCV modeling yielded consistent multivariate prognostic signatures that differentiated patients with longer vs. shorter survival. The signature for the GB group consisted of IGFBP-1, IL-6, PDGF-AA, PDGF-BB, TSP-2; while the signature for the GP group consisted of CRP, IGFBP-1, PAI-1, PDGF-AA, PEDF (both p<0.0001). Three potential predictive markers of superior OS for GB vs. GP were identified: VEGF-D (p<0.01), SDF-1b (p<0.05), and Ang2 (p<0.05). Spearman's rank correlation coefficients suggested that many factors were co-regulated.This is one of the first phase III studies to report multiplex angiome profiling and it shows that tumor angiogenesis factors are highly prognostic in patients with PC. Several of these factors may define those pts more or less likely to benefit from the addition of B to G. This information should allow better stratification of patients with PC and may guide novel therapeutic interventions in PC and perhaps other cancers.

Authors
Nixon, AB; Pang, H; Starr, M; Hollis, D; Friedman, PN; Bertagnolli, MM; Kindler, HL; Goldberg, RM; Venook, AP; Hurwitz, H
MLA Citation
Nixon, AB, Pang, H, Starr, M, Hollis, D, Friedman, PN, Bertagnolli, MM, Kindler, HL, Goldberg, RM, Venook, AP, and Hurwitz, H. "Prognostic and predictive blood-based biomarkers in patients with advanced pancreatic cancer: Results from CALGB 80303." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29.15_suppl (May 2011): 10508-.
PMID
28022380
Source
epmc
Published In
Journal of Clinical Oncology
Volume
29
Issue
15_suppl
Publish Date
2011
Start Page
10508

A phase II study of capecitabine, oxaliplatin, bevacizumab and cetuximab in the treatment of metastatic colorectal cancer.

AIM: This study was designed to determine the efficacy and tolerability of capecitabine, oxaliplatin and bevacizumab in combination with cetuximab as first-line therapy for advanced colorectal cancer. PATIENTS AND METHODS: Patients with previously untreated advanced colorectal cancer received oxaliplatin 130 mg/m² and bevacizumab 7.5 mg/kg every three weeks, capecitabine 850 mg/m² twice daily on days 1-14, and cetuximab at 400 mg/m² load and 250 mg/m² weekly. KRAS, BRAF and PI3K mutation status from paraffin-embedded tumor samples were assessed using real-time polymerase chain reaction. RESULTS: Thirty patients were evaluable for safety and efficacy. One patient had a complete response and 12 patients had a partial response, giving an overall response rate of 43% (95% confidence interval (CI) 25%-63%). Fifteen patients had stable disease. The median time to progression was 10.3 months (95% CI, 6.8-16.3 months). The median overall survival was 18.8 months (95% CI, 14.2-23.7 months). Common grade ≥ 3 non-hematological toxicities were skin rash (37%), sensory neuropathy (27%) and diarrhea (17%). Grade ≥ 3 hematological toxicities were uncommon. Mutations in KRAS, BRAF and PI3K occurred in 34.5%, 10.3% and 10.3% of patients respectively, but did not correlate with treatment outcome. CONCLUSION: The addition of cetuximab to capecitabine, oxaliplatin and bevacizumab did not improve the three-drug regimen activity compared to published data and was associated with significant toxicities requiring frequent dose modifications. KRAS, BRAF, and PI3K mutation status were consistent with published literature, but did not affect outcome in this small study.

Authors
Wong, NS; Fernando, NH; Nixon, AB; Cushman, S; Aklilu, M; Bendell, JC; Morse, MA; Blobe, GC; Ashton, J; Pang, H; Hurwitz, HI
MLA Citation
Wong, NS, Fernando, NH, Nixon, AB, Cushman, S, Aklilu, M, Bendell, JC, Morse, MA, Blobe, GC, Ashton, J, Pang, H, and Hurwitz, HI. "A phase II study of capecitabine, oxaliplatin, bevacizumab and cetuximab in the treatment of metastatic colorectal cancer." Anticancer Res 31.1 (January 2011): 255-261.
PMID
21273607
Source
pubmed
Published In
Anticancer research
Volume
31
Issue
1
Publish Date
2011
Start Page
255
End Page
261

Effect of pazopanib on tumor microenvironment and liposome delivery.

Pathologic angiogenesis creates an abnormal microenvironment in solid tumors, characterized by elevated interstitial fluid pressure (IFP) and hypoxia. Emerging theories suggest that judicious downregulation of proangiogenic signaling pathways may transiently "normalize" the vascular bed, making it more suitable for drug delivery and radiotherapy. In this work, we investigate the role of pazopanib, a small-molecule inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, on tumor IFP, angiogenesis, hypoxia, and liposomal drug delivery. Nude mice bearing A549 human non-small cell lung cancer xenografts were treated with 100 mg/kg pazopanib (n = 20) or vehicle (n = 20) through oral gavage for 8 days, followed by a one-time intravenous dose of 10 mg/kg Doxil (liposomal doxorubicin). Pazopanib treatment resulted in significant reduction of tumor IFP and decreased vessel density, assessed by CD31 staining. Despite these trends toward normalization, high-performance liquid chromatography revealed no differences in doxorubicin concentration between pazopanib-treated and control tumors, with Doxil penetration from microvessels being significantly reduced in the pazopanib group. Additionally, tumor hypoxia, evaluated by CA-IX immunostaining and confirmed in a second study by EF5 expression (n = 4, 100 mg/kg pazopanib; n = 4, vehicle), was increased in pazopanib-treated tumors. Our results suggest that the classic definition of tumor "normalization" may undermine the crucial role of vessel permeability and oncotic pressure gradients in liposomal drug delivery, and that functional measures of normalization, such as reduced IFP and hypoxia, may not occur in parallel temporal windows.

Authors
Tailor, TD; Hanna, G; Yarmolenko, PS; Dreher, MR; Betof, AS; Nixon, AB; Spasojevic, I; Dewhirst, MW
MLA Citation
Tailor, TD, Hanna, G, Yarmolenko, PS, Dreher, MR, Betof, AS, Nixon, AB, Spasojevic, I, and Dewhirst, MW. "Effect of pazopanib on tumor microenvironment and liposome delivery." Mol Cancer Ther 9.6 (June 2010): 1798-1808.
PMID
20515941
Source
pubmed
Published In
Molecular cancer therapeutics
Volume
9
Issue
6
Publish Date
2010
Start Page
1798
End Page
1808
DOI
10.1158/1535-7163.MCT-09-0856

A phase I dose-escalation study of imatinib mesylate (Gleevec/STI571) plus capecitabine (Xeloda) in advanced solid tumors.

UNLABELLED: The aim of this study was to determine the maximally tolerated dose, recommended phase II dose and toxicity profile of capecitabine plus imatinib mesylate combination. PATIENTS AND METHODS: Twenty-four patients with advanced solid tumors were treated with capecitabine twice daily on days 1-14 and imatinib mesylate once daily on a 21-day cycle. Dose-limiting toxicity was assessed during the first cycle. Treatment continued until disease progression or undesirable toxicity. RESULTS: Six patients were treated with capecitabine at 1000 mg/m(2) and imatinib mesylate 300 mg; unacceptable toxicity due to grade 2 intolerable hand-foot syndrome and/or grade > or = 2 diarrhea was observed. Doses were subsequently reduced to capecitabine at 750 mg/m(2) and imatinib mesylate at 300 mg; toxicities were better tolerated at the lower dose. Dose-limiting toxicities consisted of grade 3 diarrhea, anorexia and fatigue lasting > or = 4 days. Treatment-related adverse events greater than or equal to grade 3 included anemia, diarrhea, dysuria, hypophosphatemia and vertigo. Minor responses were observed in two patients: stable disease > or = 6 months was observed in two out of twenty-one evaluable patients. CONCLUSION: Full doses of capecitabine and imatinib mesylate were not tolerable. The maximum tolerated dose and the recommended phase II dose for this drug combination is capecitabine at 750 mg/m(2) twice daily for 1-14 days and imatinib at 300 mg once daily on a 21-day cycle.

Authors
Dugan, E; Truax, R; Meadows, KL; Nixon, AB; Petros, WP; Favaro, J; Fernando, NH; Morse, MA; Blobe, GC; Hurwitz, HI
MLA Citation
Dugan, E, Truax, R, Meadows, KL, Nixon, AB, Petros, WP, Favaro, J, Fernando, NH, Morse, MA, Blobe, GC, and Hurwitz, HI. "A phase I dose-escalation study of imatinib mesylate (Gleevec/STI571) plus capecitabine (Xeloda) in advanced solid tumors." Anticancer Res 30.4 (April 2010): 1251-1256.
PMID
20530436
Source
pubmed
Published In
Anticancer research
Volume
30
Issue
4
Publish Date
2010
Start Page
1251
End Page
1256

Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression.

Drugs and antibodies that interrupt vascular endothelial growth factor (VEGF) signaling pathways improve outcomes in patients with a variety of cancers by inhibiting tumor angiogenesis. A major adverse effect of these treatments is hypertension, suggesting a critical role for VEGF in blood pressure (BP) regulation. However, the physiological mechanisms underlying the control of BP by VEGF are unclear. To address this question, we administered a specific antibody against the major VEGF receptor, VEGFR2, to normal mice and assessed the consequences on BP. Compared with vehicle-treated controls, administration of the anti-VEGFR2 antibody caused a rapid and sustained increase in BP of approximately 10 mm Hg. This increase in BP was associated with a significant reduction in renin mRNA expression in the kidney (P=0.019) and in urinary excretion of aldosterone (P<0.05). Treatment with the anti-VEGFR2 antibody also caused a marked reduction in the expression of endothelial and neuronal NO synthases in the kidney. To examine the role of NO in the hypertension caused by blocking VEGFR2, mice were treated with N(omega)-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg per day), an inhibitor of NO production. L-NAME administration abolished the difference in BP between the vehicle- and anti-VEGFR2-treated groups. Our data suggest that VEGF, acting via VEGFR2, plays a critical role in BP control by promoting NO synthase expression and NO activity. Interfering with this pathway is likely to be one mechanism underlying hypertension caused by antiangiogenic agents targeting VEGF.

Authors
Facemire, CS; Nixon, AB; Griffiths, R; Hurwitz, H; Coffman, TM
MLA Citation
Facemire, CS, Nixon, AB, Griffiths, R, Hurwitz, H, and Coffman, TM. "Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression." Hypertension 54.3 (September 2009): 652-658.
PMID
19652084
Source
pubmed
Published In
Hypertension
Volume
54
Issue
3
Publish Date
2009
Start Page
652
End Page
658
DOI
10.1161/HYPERTENSIONAHA.109.129973

Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC)

Authors
Bullock, KE; Hurwitz, HI; Uronis, HE; Morse, MA; Blobe, GC; Hsu, SD; Zafar, SY; Nixon, AB; Howard, LA; Bendell, JC
MLA Citation
Bullock, KE, Hurwitz, HI, Uronis, HE, Morse, MA, Blobe, GC, Hsu, SD, Zafar, SY, Nixon, AB, Howard, LA, and Bendell, JC. "Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC)." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors

Authors
Howard, LA; Bullock, KE; Bendell, JC; Uronis, HE; Vlahovic, G; Blobe, GC; Riedel, RF; Nixon, AB; Gockerman, JP; Hurwitz, HI
MLA Citation
Howard, LA, Bullock, KE, Bendell, JC, Uronis, HE, Vlahovic, G, Blobe, GC, Riedel, RF, Nixon, AB, Gockerman, JP, and Hurwitz, HI. "Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Dual inhibition of alpha(V) integrins and Src kinase activity in colon cancer cells

Authors
Starodub, A; Jia, J; Cushman, S; Marshall, D; Hurwitz, HI; Nixon, AB
MLA Citation
Starodub, A, Jia, J, Cushman, S, Marshall, D, Hurwitz, HI, and Nixon, AB. "Dual inhibition of alpha(V) integrins and Src kinase activity in colon cancer cells." May 20, 2009.
Source
wos-lite
Published In
Journal of Clinical Oncology
Volume
27
Issue
15
Publish Date
2009

Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC).

4080 Background: For patients (pts) with mCRC, no standard therapy exists after progression on 5-FU, oxaliplatin, irinotecan, bevacizumab, and/or cetuximab/panitumumab. Preclinical data demonstrate combined VEGF and mTOR inhibition has greater anti-angiogenic and anti-tumor activity than either monotherapy. B inhibits VEGF; E inhibits mTOR. Phase I data in patients demonstrated B + E was safe and activity was seen in several pts with refractory mCRC.25 pts with refractory mCRC were enrolled in an expanded cohort of B + E. Doses: B 10 mg/kg q2 wks; E 10 mg PO QD. Blood, skin, and tumor biopsies pre- and on-treatment were collected for markers of response and resistance.At this time, 19 pts (10M: 9F) are evaluable for toxicity; 17 for efficacy. Median age 57 years (range 35-78). Median number prior regimens 3. All pts had prior B exposure; 17 pts had progressive disease on prior B-based therapy. There was one Grade (Gr) 4 adverse event (AE) of hypokalemia. Grade 3 AE related to treatment were bowel perforation/fistula, (n=2), hyperglycemia (3), hypokalemia (3), hypertension (2), fatigue (1), alk phos elevation (1; lab only), hypoalbuminemia (1), and volume depletion (1). Other events of interest were: Gr1-2 mucositis (n=10), Gr1 hyperlipidemia (11). Of 17 pts evaluable for response, 4 pts had SD as best response (median 24 wks, range 17-31+ wks); there were 3 minor responses in pts who had progressed on B (median 16 wks, range 16-27 wks). No CR or PR were seen. Biomarker data is pending.B+E has activity in refractory mCRC in pts who had progressed on a B-based regimen, suggesting B+E may overcome resistance to B. Patient accrual is continuing and updated data will be presented. [Table: see text].

Authors
Bullock, KE; Hurwitz, HI; Uronis, HE; Morse, MA; Blobe, GC; Hsu, SD; Zafar, SY; Nixon, AB; Howard, LA; Bendell, JC
MLA Citation
Bullock, KE, Hurwitz, HI, Uronis, HE, Morse, MA, Blobe, GC, Hsu, SD, Zafar, SY, Nixon, AB, Howard, LA, and Bendell, JC. "Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC)." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 4080-.
PMID
27961646
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
4080

Dual inhibition of αV integrins and Src kinase activity in colon cancer cells.

e14609 Background: Integrins are commonly upregulated in tumor cells and are important regulators of invasion and metastasis. Integrin signaling is initiated upon engagement of ECM and requires Src as well as various other proteins including ILK, FAK, and paxillin.Presence of αv integrins on CRC cell lines was established by flow cytometry. CNTO 95 (10μg/ml, a monoclonal anti-αv integrin antibody; Ortho Biotech), and dasatinib (<200nM; BMS, src small molecule inhibitor) were used to study the effects of combined integrin and src inhibition on proliferation and serum-induced migration of colon cancer cell lines in vitro. Downstream signaling changes were assessed by immunoblotting for phosphorylated forms of src, FAK (Y397, Y576/577 and Y925), paxillin, GSK3β and AKT (S473) in HT29, HCT116 and RKO.Proliferation was inhibited by dasatinib in HT29, HCT116, DLD1 and HCT15 in a dose-dependent manner, while RKO and SW48 were resistant. Combining CNTO 95 with dasatinib further inhibited proliferation in all dasatinib-sensitive cells, yet resistant cells were unaffected. Migration was blocked by both CNTO 95 and dasatinib in all cell lines, and combining the two drugs produced augmented effect. Src activation and src- dependent FAK phosphorylation at sites 576 and 925 were blocked by dasatinib; CNTO 95 had little effect alone, but potentiated the effect of dasatinib. Paxillin phosphorylation was modestly blocked by both compounds, but the combination produced significantly augmented inhibition in the three cell lines tested. The phosphorylation status of AKT and GSK-3β, which are downstream of ILK, was inhibited by both drugs as single agents. The combination of dasatinib and CNTO 95 produced further inhibition.Dual inhibition of Src by dasatinib and αv integrins by CNTO 95 produced additive to synergistic inhibition of proliferation in dasatinib sensitive CRC cell lines, and inhibition of migration in all cell lines tested. Decreased phospho-paxillin levels may be responsible for the pronounced inhibition of migration observed after dual treatment with dasatinib and CNTO 95 in these CRC cell lines. These data support the rationale for combined Src/integrin inhibition in colon cancer, and further suggest approaches to patient selection strategies. [Table: see text].

Authors
Starodub, A; Jia, J; Cushman, S; Marshall, D; Hurwitz, HI; Nixon, AB
MLA Citation
Starodub, A, Jia, J, Cushman, S, Marshall, D, Hurwitz, HI, and Nixon, AB. "Dual inhibition of αV integrins and Src kinase activity in colon cancer cells." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): e14609-.
PMID
27964163
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
e14609

Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors.

3551 Background: In preclinical models, VEGF, mTOR, and EGFR inhibitors have anti-tumor and anti-angiogenesis effects as monotherapies and in combination. B inhibits VEGF; E inhibits mTOR; P inhibits EGFR. There is also potential for interaction between the pathways. Previously BE and BE + erlotinib were evaluated and showed signs of clinical activity.Patients (pts) with refractory advanced solid tumors were accrued in a phase I dose escalation of B + E + P on a 28d cycle. Dose levels are shown in the table below. DLT was defined as any treatment-related grade 4 heme, grade 3/4 non-heme adverse event (AE), or receiving <85% any study drug in Cycle 1. Blood, skin, and tumor biopsies pre- and on-treatment were collected for correlative biomarkers of angiogenesis.At this time, 12 pts (3M: 9F) are evaluable for toxicity; 9 for efficacy. Median age: 54 years (range 23-72). 9 of 12 pts had prior B exposure. Dose level 1 was expanded due to 1/3 DLT, with total of 3/6 DLT (Grade (Gr) 3 mucositis (n=2), Gr3 hypokalemia (n=1)). Dose level -1 had 3/3 DLT (Gr3, Gr4 mucositis (n=2), Gr3 non-acneform rash (n=1)). Dose level -2 had 0/3 pts DLT. Gr 3-4 related toxicities in cycle 2+: hypokalemia (n=4); hypophosphatemia (n = 1); hypomagnesemia (n = 1); diarrhea (n=1); hoarseness (n=1). Other events of interest were: Gr1-2 mucositis (n=7); Gr1 hyperlipidemia (n=5); Gr1-2 hyperglycemia (n=4); Gr2 hypertension (n=2); Gr1-2 neutropenia (n=5); Gr1-2 thrombocytopenia (n=5). 8/9 evaluable pts had SD as best response (median 26 wks, range 8+ to 32+ wks): 1 pt with pancreatic cancer and progression on 2 prior EGFR inhibitors had prolonged 32+ wk SD. There was 1 minor response (23.3%) in a pt with bevacizumab-refractory ovarian cancer (32+ wks). No CR or PR were seen.B + E + P at full doses has dose limiting toxicities of rash and mucositis. B 10 mg/kg q2wks + E 5 mg q48h + P 4.8 mg/kg q2wks is the maximum tolerated dose. This dose is currently being expanded in 20 patients with extensive pre- and on-treatment biomarker analyses. Updated clinical and biomarker data will be presented. [Table: see text] [Table: see text].

Authors
Howard, LA; Bullock, KE; Bendell, JC; Uronis, HE; Vlahovic, G; Blobe, GC; Riedel, RF; Nixon, AB; Gockerman, JP; Hurwitz, HI
MLA Citation
Howard, LA, Bullock, KE, Bendell, JC, Uronis, HE, Vlahovic, G, Blobe, GC, Riedel, RF, Nixon, AB, Gockerman, JP, and Hurwitz, HI. "Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors." Journal of clinical oncology : official journal of the American Society of Clinical Oncology 27.15_suppl (May 2009): 3551-.
PMID
27961368
Source
epmc
Published In
Journal of Clinical Oncology
Volume
27
Issue
15_suppl
Publish Date
2009
Start Page
3551

The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients.

Impairment of dendritic cells (DC), the most effective activators of anticancer immune responses, is one mechanism for defective antitumor immunity, but the causes of DC impairment are incompletely understood. We evaluated the association of impaired DC differentiation with angiogenesis-associated molecules D-dimer, vascular endothelial growth factor (VEGF), urokinase plasminogen activator (uPA), and plasminogen activator inhibitor (PAI-1) in peripheral blood from 41 patients with lung, breast, and colorectal carcinoma. Subsequently, we studied the effect of administration of the anti-VEGF antibody (bevacizumab) on DC maturation and function in vivo. Compared with healthy volunteers, cancer patients had a bias toward the immunoregulatory DC2, had deficits in DC maturation after overnight in vitro culture, and had a significant increase in immature myeloid cell progenitors of DC (0.50 +/- 0.31% vs. 0.32 +/- 0.16% of peripheral blood mononuclear cells, respectively, P = 0.011). A positive correlation was found between the percentage of DC2 and PAI-1 (R = 0.50) and between immature myeloid cells and VEGF (R = 0.52). Bevacizumab administration to cancer patients was associated with a decrease in the accumulation of immature progenitor cells (0.39 +/- 0.30% vs. 0.27 +/- 0.24%, P = 0.012) and induced a modest increase in the DC population in peripheral blood (0.47 +/- 0.23% vs. 0.53 +/- 0.30%). Moreover, anti-VEGF antibody treatment enhanced allo-stimulatory capacity of DC and T cell proliferation against recall antigens. These data suggest that DC differentiation is negatively associated with VEGF levels and may be one explanation for impaired anticancer immunity, especially in patients with advanced malignancies.

Authors
Osada, T; Chong, G; Tansik, R; Hong, T; Spector, N; Kumar, R; Hurwitz, HI; Dev, I; Nixon, AB; Lyerly, HK; Clay, T; Morse, MA
MLA Citation
Osada, T, Chong, G, Tansik, R, Hong, T, Spector, N, Kumar, R, Hurwitz, HI, Dev, I, Nixon, AB, Lyerly, HK, Clay, T, and Morse, MA. "The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients." Cancer Immunol Immunother 57.8 (August 2008): 1115-1124.
PMID
18193223
Source
pubmed
Published In
Cancer Immunology, Immunotherapy
Volume
57
Issue
8
Publish Date
2008
Start Page
1115
End Page
1124
DOI
10.1007/s00262-007-0441-x

A role for G(z) in pancreatic islet beta-cell biology.

Glucose-stimulated insulin secretion and beta-cell growth are important facets of pancreatic islet beta-cell biology. As a result, factors that modulate these processes are of great interest for the potential treatment of Type 2 diabetes. Here, we present evidence that the heterotrimeric G protein G(z) and its effectors, including some previously thought to be confined in expression to neuronal cells, are present in pancreatic beta-cells, the largest cellular constituent of the islets of Langerhans. Furthermore, signaling pathways upon which G alpha(z) impacts are intact in beta-cells, and G alpha(z) activation inhibits both cAMP production and glucose-stimulated insulin secretion in the Ins-1(832/13) beta-cell-derived line. Inhibition of glucose-stimulated insulin secretion by prostaglandin E (PGE1) is pertussis-toxin insensitive, indicating that other G alpha(i) family members are not involved in this process in this beta-cell line. Indeed, overexpression of a selective deactivator of G alpha(z), the RGS domain of RGSZ1, blocks the inhibitory effect of PGE1 on glucose-stimulated insulin secretion. Finally, the inhibition of glucose-stimulated insulin secretion by PGE1 is substantially blunted by small interfering RNA-mediated knockdown of G alpha(z) expression. Taken together, these data strongly imply that the endogenous E prostanoid receptor in the Ins-1(832/13) beta-cell line couples to G(z) predominantly and perhaps even exclusively. These data provide the first evidence for G(z) signaling in pancreatic beta-cells, and identify an endogenous receptor-mediated signaling process in beta-cells that is dependent on G alpha(z) function.

Authors
Kimple, ME; Nixon, AB; Kelly, P; Bailey, CL; Young, KH; Fields, TA; Casey, PJ
MLA Citation
Kimple, ME, Nixon, AB, Kelly, P, Bailey, CL, Young, KH, Fields, TA, and Casey, PJ. "A role for G(z) in pancreatic islet beta-cell biology." J Biol Chem 280.36 (September 9, 2005): 31708-31713.
PMID
16157560
Source
pubmed
Published In
The Journal of biological chemistry
Volume
280
Issue
36
Publish Date
2005
Start Page
31708
End Page
31713
DOI
10.1074/jbc.M506700200

Analysis of the regulation of microtubule dynamics by interaction of RGSZ1 (RGS20) with the neuronal stathmin, SCG10.

Regulators of G protein signaling (RGS proteins) are a diverse family of proteins that act to negatively regulate signaling by heterotrimeric G proteins; however, recent data have implied additional functions for RGS proteins. Previously, we employed the yeast two-hybrid system and identified the microtubule-destabilizing protein, superior cervical ganglia neural-specific 10 protein (SCG10), as a potential effector protein of RGSZ1. This article describes the expression and biochemical purification of both RGSZ1 and SCG10 and details the development of various in vitro assays to evaluate microtubule polymerization?depolymerization. Both turbidimetric and microscopy-based assays can be employed to study the impact that RGS proteins have on SCG10 function. The application of these in vitro assays may help identify a novel role for RGS proteins in regulating the cytoskeletal network.

Authors
Nixon, AB; Casey, PJ
MLA Citation
Nixon, AB, and Casey, PJ. "Analysis of the regulation of microtubule dynamics by interaction of RGSZ1 (RGS20) with the neuronal stathmin, SCG10." Methods Enzymol 390 (2004): 53-64.
PMID
15488170
Source
pubmed
Published In
Methods in Enzymology
Volume
390
Publish Date
2004
Start Page
53
End Page
64
DOI
10.1016/S0076-6879(04)90004-3

The interaction of RGSZ1 with SCG10 attenuates the ability of SCG10 to promote microtubule disassembly.

RGS proteins (regulators of G protein signaling) are a diverse family of proteins that act to negatively regulate signaling by heterotrimeric G proteins. Initially characterized as GTPase-activating proteins for Galpha subunits, recent data have implied additional functions for RGS proteins. We previously identified an RGS protein (termed RGSZ1) whose expression is quite specific to neuronal tissue (Glick, J. L., Meigs, T. E., Miron, A., and Casey, P. J. (1998) J. Biol. Chem. 273, 26008-26013). In a continuing effort to understand the role of RGSZ1 in cellular signaling, the yeast two-hybrid system was employed to identify potential effector proteins of RGSZ1. The microtubule-destabilizing protein SCG10 (superior cervical ganglia, neural specific 10) was found to directly interact with RGSZ1 in the yeast system, and this interaction was further verified using direct binding assays. Treatment of PC12 cells with nerve growth factor resulted in Golgi-specific distribution of SCG10. A green fluorescent protein-tagged variant of RGSZ1 translocated to the Golgi complex upon treatment of PC12 cells with nerve growth factor, providing evidence that RGSZ1 and SCG10 interact in cells as well as in vitro. Analysis of in vitro microtubule polymerization/depolymerization showed that binding of RGSZ1 to SCG10 effectively blocked the ability of SCG10 to induce microtubule disassembly as determined by both turbidimetric and microscopy-based assays. These results identify a novel connection between RGS proteins and the cytoskeletal network that points to a broader role than previously envisioned for RGS proteins in regulating biological processes.

Authors
Nixon, AB; Grenningloh, G; Casey, PJ
MLA Citation
Nixon, AB, Grenningloh, G, and Casey, PJ. "The interaction of RGSZ1 with SCG10 attenuates the ability of SCG10 to promote microtubule disassembly." J Biol Chem 277.20 (May 17, 2002): 18127-18133.
PMID
11882662
Source
pubmed
Published In
The Journal of biological chemistry
Volume
277
Issue
20
Publish Date
2002
Start Page
18127
End Page
18133
DOI
10.1074/jbc.M201065200

Regulation of platelet-activating factor synthesis in human neutrophils by MAP kinases

Human neutrophils (PMN) are potentially a major source of platelet-activating factor (PAF) produced during inflammatory responses. The stimulated synthesis of PAF in PMN is carried out by a phospholipid remodeling pathway involving three enzymes: acetyl-CoA:lyso-PAF acetyltransferase (acetyltransferase), type IV phospholipase A2 (cPLA2) and CoA-independent transacylase (CoA-IT). However, the coordinated actions and the regulatory mechanisms of these enzymes in PAF synthesis are poorly defined. A23187 has been widely used to activate the remodeling pathway, but it has not been shown how closely its actions mimic those of physiological stimuli. Here we address this important problem and compare responses of the three remodeling enzymes and PAF synthesis by intact cells. In both A23187- and N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMN, acetyltransferase activation is blocked by SB 203580, a p38 MAP kinase inhibitor, but not by PD 98059, which blocks activation of the ERKs. In contrast, either agent attenuated cPLA2 activation. Correlating with these results, SB 203580 decreased stimulated PAF formation by 60%, whereas PD 98059 had little effect. However, the combination of both inhibitors decreased PAF formation to control levels. Although a role for CoA-IT in PAF synthesis is recognized, we did not detect activation of the enzyme in stimulated PMN. CoA-IT thus appears to exhibit full activity in resting as well as stimulated cells. We conclude that the calcium ionophore A23187 and the receptor agonist fMLP both act through common pathways to stimulate PAF synthesis, with p38 MAP kinase regulating acetyltransferase and supplementing ERK activation of cPLA2. © 2002 Elsevier Science B.V. All rights reserved.

Authors
Baker, PRS; Owen, JS; Nixon, AB; Thomas, LN; Wooten, R; Daniel, LW; O'Flaherty, JT; Wykle, RL
MLA Citation
Baker, PRS, Owen, JS, Nixon, AB, Thomas, LN, Wooten, R, Daniel, LW, O'Flaherty, JT, and Wykle, RL. "Regulation of platelet-activating factor synthesis in human neutrophils by MAP kinases." Biochimica et Biophysica Acta - Molecular Cell Research 1592.2 (2002): 175-184.
PMID
12379481
Source
scival
Published In
BBA - Molecular Cell Research
Volume
1592
Issue
2
Publish Date
2002
Start Page
175
End Page
184
DOI
10.1016/S0167-4889(02)00314-2

HDAC6 is a microtubule-associated deacetylase

Reversible acetylation of α-tubulin has been implicated in regulating microtubule stability and function. The distribution of acetylated α-tubulin is tightly controlled and stereotypic. Acetylated α-tubulin is most abundant in stable microtubules but is absent from dynamic cellular structures such as neuronal growth cones and the leading edges of fibroblasts. However, the enzymes responsible for regulating tubulin acetylation and deacetylation are not known. Here we report that a member of the histone deacetylase family, HDAC6, functions as a tubulin deacetylase. HDAC6 is localized exclusively in the cytoplasm, where it associates with microtubules and localizes with the microtubule motor complex containing p150glued (ref. 3). In vivo, the overexpression of HDAC6 leads to a global deacetylation of α-tubulin, whereas a decrease in HDAC6 increases α-tubulin acetylation. In vitro, purified HDAC6 potently deacetylates α-tubulin in assembled microtubules. Furthermore, overexpression of HDAC6 promotes chemotactic cell movement, supporting the idea that HDAC6-mediated deacetylation regulates microtubule-dependent cell motility. Our results show that HDAC6 is the tubulin deacetylase, and provide evidence that reversible acetylation regulates important biological processes beyond histone metabolism and gene transcription.

Authors
Hubbert, C; Guardiola, A; Shao, R; Kawaguchi, Y; Ito, A; Nixon, A; Yoshida, M; Wang, X-F; Yao, T-P
MLA Citation
Hubbert, C, Guardiola, A, Shao, R, Kawaguchi, Y, Ito, A, Nixon, A, Yoshida, M, Wang, X-F, and Yao, T-P. "HDAC6 is a microtubule-associated deacetylase." Nature 417.6887 (2002): 455-458.
PMID
12024216
Source
scival
Published In
Nature
Volume
417
Issue
6887
Publish Date
2002
Start Page
455
End Page
458
DOI
10.1038/417455a

Phosphorylation and nuclear translocation of a regulator of G protein signaling (RGS10).

Heterotrimeric G proteins are involved in the transduction of hormonal and sensory signals across plasma membranes of eukaryotic cells. Hence, they are a critical point of control for a variety of agents that modulate cellular function. Activation of these proteins is dependent on GTP binding to their alpha (Galpha) subunits. Regulators of G protein signaling (RGS) bind specifically to activated Galpha proteins, potentiating the intrinsic GTPase activity of the Galpha proteins and thus expediting the termination of Galpha signaling. Although there are several points in most G protein controlled signaling pathways that are affected by reversible covalent modification, little evidence has been shown addressing whether or not the functions of RGS proteins are themselves regulated by such modifications. We report in this study the acute functional regulation of RGS10 thru the specific and inducible phosphorylation of RGS10 protein at serine 168 by cAMP-dependent kinase A. This phosphorylation nullifies the RGS10 activity at the plasma membrane, which controls the G protein-dependent activation of the inwardly rectifying potassium channel. Surprisingly, the phosphorylation-mediated attenuation of RGS10 activity was not manifested in an alteration of its ability to accelerate GTPase activity of Galpha. Rather, the phosphorylation event correlates with translocation of RGS10 from the plasma membrane and cytosol into the nucleus.

Authors
Burgon, PG; Lee, WL; Nixon, AB; Peralta, EG; Casey, PJ
MLA Citation
Burgon, PG, Lee, WL, Nixon, AB, Peralta, EG, and Casey, PJ. "Phosphorylation and nuclear translocation of a regulator of G protein signaling (RGS10)." J Biol Chem 276.35 (August 31, 2001): 32828-32834.
PMID
11443111
Source
pubmed
Published In
The Journal of biological chemistry
Volume
276
Issue
35
Publish Date
2001
Start Page
32828
End Page
32834
DOI
10.1074/jbc.M100960200

Phosphorylation and nuclear translocation of a regulator of G-protein signaling (RGS10).

Authors
Burgon, PG; Lee, WL; Nixon, AB; Casey, PJ; Peralta, EG
MLA Citation
Burgon, PG, Lee, WL, Nixon, AB, Casey, PJ, and Peralta, EG. "Phosphorylation and nuclear translocation of a regulator of G-protein signaling (RGS10)." FASEB JOURNAL 14.8 (May 11, 2000): A1483-A1483.
Source
wos-lite
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
14
Issue
8
Publish Date
2000
Start Page
A1483
End Page
A1483

Acetyl-CoA:1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine acetyltransferase is directly activated by p38 kinase

Acetyl-CoA:1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine acetyltransferase, along with phospholipase A2, is a key regulator of platelet-activating factor biosynthesis via the remodeling pathway. We have now obtained evidence in human neutrophils indicating that this enzyme is regulated by a specific member of the mitogen-activated protein kinases, namely the p38 kinase. We earlier demonstrated that tumor necrosis factor-α (TNF-α) as well as N-formyl-methionyl-leucyl-phenylalanine treatment leads to increased phosphorylation and activation of p38 kinase in human neutrophils. Strikingly, in the present study these stimuli increased the catalytic activity of acetyltransferase up to 3-fold, whereas 4-phorbol 12- myristate 13-acetate, which activates the extracellular-regulated kinases (ERKs) but not p38 kinase, had no effect. Furthermore, a selective inhibitor of p38 kinase, SB 203580, was able to abolish the TNF-α- and N-formyl- methionyl-leucyl-phenylalanine-induced activation of acetyltransferase. The same effect was not observed in the presence of an inhibitor that blocked ERK activation (PD 98059). Complementing the findings in intact cells, we have shown that recombinant, activated p38 kinase added to microsomes in the presence of Mg2+ and ATP increased acetyltransferase activity to the same degree as in microsomes obtained from TNF-α-stimulated cells. No activation of acetyltransferase occurred upon treatment of microsomes with either recombinant, activated ERK-1 or ERK-2. Finally, the increases in acetyltransferase activity induced by TNF-α could be ablated by treating the microsomes with alkaline phosphatase. Thus acetyltransferase appears to be a downstream target for p38 kinase but not ERKs. These data from whole cells as well as cell-free systems fit a model wherein stimulus-induced acetyltransferase activation is mediated by a phosphorylation event catalyzed directly by p38 kinase.

Authors
Nixon, AB; O'Flaherty, JT; Salyer, JK; Wykle, RL
MLA Citation
Nixon, AB, O'Flaherty, JT, Salyer, JK, and Wykle, RL. "Acetyl-CoA:1-O-alkyl-2-lyso-sn-glycero-3-phosphocholine acetyltransferase is directly activated by p38 kinase." Journal of Biological Chemistry 274.9 (1999): 5469-5473.
PMID
10026159
Source
scival
Published In
The Journal of biological chemistry
Volume
274
Issue
9
Publish Date
1999
Start Page
5469
End Page
5473
DOI
10.1074/jbc.274.9.5469

Differential activation of human neutrophil cytosolic phospholipase A2 and secretory phospholipase A2 during priming by 1,2-diacyl- and 1-O-alkyl-2-acylglycerols

We have shown previously that both 1,2-diacylglycerol (AAG) and 1-O-alkyl-2-acylglycerol (EAG) prime neutrophil release of arachidonic acid via uncharacterized phospholipases A2. Therefore, we investigated the actions of EAG and AAG specifically on neutrophil cytosolic (cPLA2) and secretory (sPLA2) phospholipase A2s. We hypothesized that AAG as a protein kinase activator would activate cPLA2 via phosphorylation events. EAG is antagonistic to the AAG activation of PKC, thus it was not expected to act via phosphorylation of cPLA2. Neutrophils were primed with either AAG or EAG and then stimulated with fMLP. When neutrophils were primed with 5-20 μM 1,2-diacylglycerol, a shift was observed in cPLA2 migration on SDS-PAGE gels, consistent with phosphorylation of the protein. This gel shift was not seen after exposure to EAG. AAG also caused a parallel increase in enzymatic activity of cPLA2 that was not seen with EAG. We also investigated whether either diglyceride would cause similar priming or direct secretion of sPLA2. Both AAG and EAG directly caused significant secretion of neutrophil sPLA2. EAG also increased the release of sPLA2 in cells subsequently stimulated with fMLP. Thus, AAG activated cPLA2 and stimulated secretion of sPLA2. In contrast, EAG did not activate cPLA2, but directly activated secretion of sPLA2. We also demonstrated that human synovial fluid sPLA2 increased AA release from resting and fMLP-stimulated neutrophils. Given that diglycerides prime for release of AA, PAF, and LTB4, these current data support the hypothesis that such priming may be mediated by phosphorylation dependent (cPLA2) or phosphorylation independent (e.g. secretion of sPLA2) events. Copyright (C) 1998.

Authors
Seeds, MC; Nixon, AB; Wykle, RL; Bass, DA
MLA Citation
Seeds, MC, Nixon, AB, Wykle, RL, and Bass, DA. "Differential activation of human neutrophil cytosolic phospholipase A2 and secretory phospholipase A2 during priming by 1,2-diacyl- and 1-O-alkyl-2-acylglycerols." Biochimica et Biophysica Acta - Lipids and Lipid Metabolism 1394.2-3 (1998): 224-234.
PMID
9795228
Source
scival
Published In
BBA - Lipids and Lipid Metabolism
Volume
1394
Issue
2-3
Publish Date
1998
Start Page
224
End Page
234
DOI
10.1016/S0005-2760(98)00111-8

Activation of 85 kDa PLA2 by eicosanoids in human neutrophils and eosinophils

Authors
Wykle, RL; Wijkander, J; Nixon, AB; Daniel, LW; O'Flaherty, JT
MLA Citation
Wykle, RL, Wijkander, J, Nixon, AB, Daniel, LW, and O'Flaherty, JT. "Activation of 85 kDa PLA2 by eicosanoids in human neutrophils and eosinophils." Advances in Experimental Medicine and Biology 416 (1997): 327-331.
PMID
9131168
Source
scival
Published In
Advances in experimental medicine and biology
Volume
416
Publish Date
1997
Start Page
327
End Page
331

Comparison of alkylacylglycerol vs. diacylglycerol as activators of mitogen-activated protein kinase and cytosolic phospholipase A2 in human neutrophil priming

In human neutrophils, the choline-containing phosphoglycerides contain almost equal amounts of alkylacyl- and diacyl-linked subclasses. In contrast to phosphatidylinositol hydrolysis which yields diacylglycerol, hydrolysis of choline-containing phosphoglycerides by phospholipase D coupled with phosphohydrolase yields both alkylacyl- and diacylglycerol. While diacylglycerol activates protein kinase C, alkylacylglycerol does not, and its role is unclear. Yet previous studies have shown that exogenous alkylacyl- and diacylglycerols can prime for the release of radiolabeled arachidonic acid (AA) in intact neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine. We have now examined the effects of both diacylglycerol (1-oleoyl-2-acetylglycerol; GAG) and alkylacylglycerol (1-O-hexadecyl-2-acetylglycerol; EAG) on the activation of mitogen-activated protein (MAP) kinase and the 85-kDa cytosolic phospholipase A2 (cPLA2) in human neutrophils. We observed that while OAG could effectively activate p42 and p44 MAP kinases along with cPLA2 in a time- and concentration-dependent manner, EAG could not. A novel p40 MAP kinase isoform is also present and activated in response to OAG treatment; the behavior of this MAP kinase isoform is discussed. The activation of cPLA2 and MAP kinase by 20 μM OAG could be inhibited by pretreatment with 1 μM GF-109203X, a selective inhibitor of protein kinase C. Although only OAG activated cPLA2, both OAG and EAG primed for the release of AA mass as determined by gas chromatography/mass spectrometry. The priming of AA release by OAG may be explained by the phosphorylation of cPLA2 through the activation of protein kinase C linked to MAP kinase. However, priming by EAG appears to involve a separate mechanism that is dependent on a different PLA2. Our results support a role for phospholipase D-derived products modulating the activation of cPLA2, further supporting the idea of cross-talk among various phospholipases.

Authors
Nixon, AB; Seeds, MC; Bass, DA; Smitherman, PK; O'Flaherty, JT; Daniel, LW; Wykle, RL
MLA Citation
Nixon, AB, Seeds, MC, Bass, DA, Smitherman, PK, O'Flaherty, JT, Daniel, LW, and Wykle, RL. "Comparison of alkylacylglycerol vs. diacylglycerol as activators of mitogen-activated protein kinase and cytosolic phospholipase A2 in human neutrophil priming." Biochimica et Biophysica Acta - Lipids and Lipid Metabolism 1347.2-3 (1997): 219-230.
PMID
9295167
Source
scival
Published In
BBA - Lipids and Lipid Metabolism
Volume
1347
Issue
2-3
Publish Date
1997
Start Page
219
End Page
230
DOI
10.1016/S0005-2760(97)00077-5

5-Oxo-eicosatetraenoate is a broadly active, eosinophil-selective stimulus for human granulocytes

5-Oxo-eicosatetraenoate (5-oxoETE) is gaining recognition as a chemotactic factor for eosinophilic (Eo) as well as neutrophilic (Neu) polymorphonuclear leukocytes. We found that the eicosanoid was far stronger than C5a, platelet- activating factor (PAF), leukotriene B4 (LTB4), or FMLP in stimulating Eo chemotaxis. Moreover, it had weak intrinsic degranulating effects on otherwise unstimulated Eo, produced prominent degranulation responses in Eo primed by granulocyte-macrophage CSF, and enhanced the Eo-degranulating potencies of PAF, C5a, LTB4, and FMLP by up to 10,000-fold. Low picomolar levels of 5-oxoETE also induced Eo to activate mitogen-activated protein kinases (MAPKs), as defined by shifts in the electrophoretic mobility and tyrosine phosphorylation of two immunodetectable proteins, p44 and p42.5- OxoETE was ≥100-fold weaker or unable to stimulate any of these responses in Neu. Finally, 5-oxo-15-hydroxy-ETE and 5-hydroxy-ETE activated both cell types, but were weaker than 5-oxoETE and had Eo/Neu potency ratios approaching unity. 5-OxoETE, thus, is uniquely potent and selective in promoting Eo not only to migrate, but also to release granule enzymes and activate MAPKs. By triggering MAPK activation, the eicosanoid may also influence the production of anaphylactoid lipids (e.g., PAF), arachidonic acid metabolites, and cytokines. 5-OxoETE therefore possesses a biologic profile well suited for mediating Eo-dominated allergic reactions in vivo.

Authors
O'Flaherty, JT; Kuroki, M; Nixon, AB; Wijkander, J; Yee, E; Lee, SL; Smitherman, PK; Wykle, RL; Daniel, LW
MLA Citation
O'Flaherty, JT, Kuroki, M, Nixon, AB, Wijkander, J, Yee, E, Lee, SL, Smitherman, PK, Wykle, RL, and Daniel, LW. "5-Oxo-eicosatetraenoate is a broadly active, eosinophil-selective stimulus for human granulocytes." Journal of Immunology 157.1 (1996): 336-342.
PMID
8683135
Source
scival
Published In
Journal of immunology (Baltimore, Md. : 1950)
Volume
157
Issue
1
Publish Date
1996
Start Page
336
End Page
342

Comparison of alkylacylglycerol (EAG) and diacylglycerol (AAG) as activators of map kjnase(s) and cytosolic PLA2 in human neutrophil priming

In human neutrophils, the choline-containing phosphoglycerides act as precursors of both AAG and EAG via the action of phospholipase D. Previous studies have shown that both AAG and EAG can enhance the fMLP-stimulated release of arachidonic acid (AA) in intact neutrophils, yet AAG or EAG alone could not induce its release, a defining feature of priming. Further, AAG activates protein kinase C while EAG does not, and EAG may in fact inhibit its activity. We examined the effect of both AAG and EAG on the activation of MAP kinase(s) and cytpsolic phospholipase A2 (cPLA2). We observed that AAG effectively activated MAP kinase(s) (Western analysis) and cPLA2 (activity measurements and Western analysis) in a time- and dose-dependent manner whereas EAG did not. We also observed a previously undescribed, activatable MAP kinase isoform (p40) in human neutrophils that cross-reacts with ERK-1 antibodies but not with ERK-2 or the HOG1 (p38) related isoform. The activation of cPLA2 and MAP kinase(s) by 20 μM AAG could be abolished by pretreatment with 100 nM GF-109203X, a selective inhibitor of protein kinase C. Although only AAG activated cPLA2, both AAG and EAG primed for the release of AA as determined by GC/MS. In summary, AAG activated MAP kinase(s) and cPLA2, whereas EAG did not, yet both primed for the release of AA suggesting the existence of divergent priming mechanisms for the release of AA induced by the two diglycerides.

Authors
Nixon, AB; Seeds, MC; Smilherman, PK; Bass, PA; Wvkle, RL
MLA Citation
Nixon, AB, Seeds, MC, Smilherman, PK, Bass, PA, and Wvkle, RL. "Comparison of alkylacylglycerol (EAG) and diacylglycerol (AAG) as activators of map kjnase(s) and cytosolic PLA2 in human neutrophil priming." FASEB Journal 10.6 (1996): A1254-.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
10
Issue
6
Publish Date
1996
Start Page
A1254

Comparison of alkylacylglycerol (eag) and diacylglycerol (aag) as activators of map kinase(s) and cytosolic pla2 in human neutrophil priming

In human neutrophils, the choline-containing phosphoglycerides act as precursors of both AAG and EAG via the action of phospholipase D. Previous studies have shown that both AAG and EAG can enhance the fMLP-stimulated release of arachidonic acid (AA) in intact neutrophils, yet AAG or EAG alone could not induce its release, a defining feature of priming. Further, AAG activates protein kinase C while EAG does not, and EAG may in fact inhibit its activity. We examined the effect of both AAG and EAG on the activation of MAP kinase(s) and cytosolic phospholipase AI (cPLAi). We observed that AAG effectively activated MAP kinase(s) (Western analysis) and cPLA2 (activity measurements and Western analysis) in a time- and dose-dependent manner whereas EAG did not. We also observed a previously undescribed, activatable MAP kinase isoform (p40) in human neutrophils that cross-reacts with ERK-1 antibodies but not with ERK-2 or the HOG1 (p38) related isoform. The activation of cPLAa and MAP kinase(s) by 20 UM AAG could be abolished by pretreaiment with 100 nM GF-109203X, a selective inhibitor of protein kinase C. Although only AAG activated cPLA2, both AAG and EAG primed for the release of AA as determined by GC/MS. In summary, AAG activated MAP kinase(s) and cPLA2, whereas EAG did not, yet both primed for the release of AA suggesting the existence of divergent priming mechanisms for the release of AA induced by the two diglycerides.

Authors
Nixon, AB
MLA Citation
Nixon, AB. "Comparison of alkylacylglycerol (eag) and diacylglycerol (aag) as activators of map kinase(s) and cytosolic pla2 in human neutrophil priming." FASEB Journal 10.6 (1996): A976-.
Source
scival
Published In
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume
10
Issue
6
Publish Date
1996
Start Page
A976

5-Oxo-eicosanoids and hematopoietic cytokines cooperate in stimulating neutrophil function and the mitogen-activated protein kinase pathway

The newly defined eicosatetraenoates (ETEs), 5-oxoETE and 5-oxo-15(OH)- ETE, share structural motifs, synthetic origins, and bioactions with leukotriene B4 (LTB4). All three eicosanoids stimulate Ca2+ transients and chemotaxis in human neutrophils (PMN). However, unlike LTB4, 5-oxoETE and 5- oxo-15(OH)-ETE alone cause little degranulation and no superoxide anion production. However, we show herein that, in PMN pretreated with granulocyte- macrophage or granulocyte colony-stimulating factor (GM-CSF or G-CSF), the oxoETEs become potent activators of the last responses. The oxoETEs also induce translocation of secretory vesicles from the cytosol to the plasmalemma, an effect not requiring cytokine priming. To study the mechanism of PMN activation in response to the eicosanoids, we examined the activation of mitogen-activated protein kinase (MAPK) and cytosolic phospholipase A2 (cPLA2). PMN expressed three proteins (40, 42, and 44 kDa) that reacted with anti-MAPK antibodies. The oxoETEs, LTB4, GM-CSF, and G-CSF all stimulated PMN to activate the MAPKs and cPLA2, as defined by shifts in these proteins' electrophoretic mobility and tyrosine phosphorylation of the MAPKs. However, the speed and duration of the MAPK response varied markedly depending on the stimulus. 5-OxoETE caused a very rapid and transient activation of MAPK. In contrast, the response to the cytokines was rather slow and persistent. PMN pretreated with GM-CSF demonstrated a dramatic increase in the extent of MAPK tyrosine phosphorylation and electrophoretic mobility shift in response to 5- oxoETE. Similarly, 5-oxoETE induced PMN to release some preincorporated [14C]arachidonic acid, while GM-CSF greatly enhanced the extent of this release. Thus, the synergism exhibited by these agents is prominent at the level of MAPK stimulation and phospholipid deacylation. Pertussis toxin, but not Ca2+ depletion, inhibited MAPK responses to 5-oxoETE and LTB4, indicating that responses to both agents are coupled through G proteins but not dependent upon Ca2+ transients. 15-OxoETE and 15(OH)-ETE were inactive while 5-oxo-15(OH)-ETE and 5(OH)-ETE had 3- and 10-fold less potency than 5- oxoETE, indicating a rather strict structural specificity for the 5-keto group. LY 255283, a LTB4 antagonist, blocked the responses to LTB4 but not to 5-oxoETE. Therefore, the oxoETEs do not appear to operate through the LTB4 receptor. In summary, the oxoETEs are potent activators of PMN that share some but not all activities with LTB4. The response to the oxoETEs is greatly enhanced by pretreatment with cytokines, indicating that combinations of these mediators may be very important in the pathogenesis of inflammation.

Authors
O'Flaherty, JT; Kuroki, M; Nixon, AB; Wijkander, J; Yee, E; Lee, SL; Smitherman, PK; Wykle, RL; Daniel, LW
MLA Citation
O'Flaherty, JT, Kuroki, M, Nixon, AB, Wijkander, J, Yee, E, Lee, SL, Smitherman, PK, Wykle, RL, and Daniel, LW. "5-Oxo-eicosanoids and hematopoietic cytokines cooperate in stimulating neutrophil function and the mitogen-activated protein kinase pathway." Journal of Biological Chemistry 271.30 (1996): 17821-17828.
PMID
8663432
Source
scival
Published In
The Journal of biological chemistry
Volume
271
Issue
30
Publish Date
1996
Start Page
17821
End Page
17828
DOI
10.1074/jbc.271.30.17821

Comparison of acceptor and donor substrats in the CoA-independent transacylase reaction in human neutrophils

In human neutrophils (PMN) the ethanolamine-containing phosphoglyceride fraction (PE), principally plasmalogen-linked PE (1-O-alk-1'-enyl-2-acyl-sn-glycero-3-phosphoethanolamine), is the major store of arachidonic acid (AA). Exogenous AA is initially incorporated into 1-acyl-linked phosphoglycerides and is believed to be transferred into the 1-ether-linked phosphoglycerides via the action of a CoA-independent transacylase (CoA-IT). We have investigated the selectivity for both the 'acceptor' lysophospholipids and 'donor' AA-containing phospholipid substrates in the CoA-IT reaction. Evidence suggests CoA-IT may also participate in the synthesis of platelet activating factor. The transfer of [3H]AA from endogenously labeled choline-containing phosphoglycerides (PC) to exogenously added alkenyl-lyso-PE (0-50 μM) was examined in saponin-permeabilized PMN. In these 'donor' studies, we observed that [3H]AA was transferred from both alkyl- and diacyl-linked PC in a proportional manner. More detailed molecular species analysis showed that [3H]AA was deacylated from all the major AA-containing molecular species in both the alkyl and diacyl subclasses with no selectivity for either subclass. To investigate the 'acceptor' selectivity, membrane fractions prelabeled with either [3H]alkyl-arachidonoyl-PE or -PC were utilized as donor substrates. Various unlabeled lysophospholipids (10 μM) were added and the generation of [3H]lyso-PE or -PC was monitored as a measure of CoA-IT activity. Significant subclass preference was observed upon addition of lyso-PE species (1-alkenyl > 1-alkyl > 1-acyl) however, little selectivity was seen with the corresponding lyse-PC species. On the other hand, lysophosphatidylserine, lysophosphatidylinositol, and lysophosphatidic acid all served as poor acceptor substrates in the reaction. These data from PMN are consistent with other evidence that the CoA-IT plays a pivotal role in the enrichment of AA into plasmalogen-linked PE.

Authors
Nixon, AB; Greene, DG; Wykle, RL
MLA Citation
Nixon, AB, Greene, DG, and Wykle, RL. "Comparison of acceptor and donor substrats in the CoA-independent transacylase reaction in human neutrophils." Biochimica et Biophysica Acta - Lipids and Lipid Metabolism 1300.3 (1996): 187-196.
PMID
8679683
Source
scival
Published In
BBA - Lipids and Lipid Metabolism
Volume
1300
Issue
3
Publish Date
1996
Start Page
187
End Page
196
DOI
10.1016/0005-2760(96)00011-2

Differential activation of human neutrophil cytosolic and secretory phospholipase a2 's during priming by 1,2-DIACYL- And 1O-ALKYL-2-Acylglycerols

Diglycerides may act as signaling molecules during inflammation and can prime cellular responses. Both 1,2-diacylglycerol (AAG) and ether linked 1-0-alkyl-2acylglycerol (EAG) prime neutrophil functions, especially the fMLP stimulated oxidative burst and arachidonic acid release. The increased AA release results from priming of phospholipase A2. Two calcium dependent phospholipase A2's have been described recently in leukocytes. They are a cytosolic phosphoprotein (cPLA2) and a low molecular weight secretory PLA2 (sPLA2). We hypothesized that AAG, a kinase activator, would activate the cPLA2 by phosphorylation. EAG is not a kinase activator and was expected to act independently of cPLA2. We recently found sPLA2 secretion can be primed by cytokines such as TNF, thus we hypothesized that EAG primed neutrophil AA release similarly may occur via activation of sPLA2. When neutrophils were primed with 5-20 &iM AAG, a shift was observed in cPLA2 migration on SDS/PAGE gels, consistent with phosphorylation of the protein. At 20 nM AAG, 86% of cPLA2 was phosphorylated. This gel shift was not activated by EAG. AAG also caused a parallel increase in enzymatic activity of cPLA2 (172+28% of resting cytosolic activity) whereas EAG did not. However, both EAG and AAG caused direct secretion of sPLA2, while only EAG further primed sPLA2 secretion upon stimulation of cells with fMLP. In summary, diglycerides can differentially activate cPLA2 (induced by AAG) and cause secretion of sPLA2 (by EAG and AAG). Also, priming by diglycerides may be kinase dependent (cPLA2) or kinase independent (sPLA2).

Authors
Seeds, MC; Nixon, AB; Wykle, RL; Bass, DA
MLA Citation
Seeds, MC, Nixon, AB, Wykle, RL, and Bass, DA. "Differential activation of human neutrophil cytosolic and secretory phospholipase a2 's during priming by 1,2-DIACYL- And 1O-ALKYL-2-Acylglycerols." Journal of Investigative Medicine 44.3 (1996): 269a-.
Source
scival
Published In
Journal of Investigative Medicine
Volume
44
Issue
3
Publish Date
1996
Start Page
269a

5-Lipoxygenase products modulate the activity of the 85-kDa phospholipase A2 in human neutrophils

Addition of submicromolar concentrations of arachidonic acid (AA) to human neutrophils induced a 2-fold increase in the activity of a cytosolic phospholipase A2 (PLA2) when measured using sonicated vesicles of 1- stearoyl-2-[14C]arachidonoylphosphatidylcholine as substrate. A similar increase in cytosolic PLA2 activity was induced by stimulation of neutrophils with leukotriene B4 (LTB4), 5-oxoeicosatetraenoic acid, or 5- hydroxyeicosatetraenoic acid (5-HETE). LTB4 was the most potent of the agonists, showing maximal effect at 1 nM. Inhibition of 5-lipoxygenase with either eicosatetraynoic acid or zileuton prevented the AA-induced increase in PLA2 activity but had no effect on the response induced by LTB4. Furthermore, pretreatment of neutrophils with a LTB4-receptor antagonist, LY 255283, blocked the AA-and LTB-induced activation of PLA2 but did not influence the action of 5-HETE. Treatment of neutrophils with pancreatic PLA2 also induced an increase in the activity of the cytosolic PLA2; this response was inhibited by both eicosatetraynoic acid or LY 255283. The increases in PLA2 activity in response to stimulation correlated with a shift in electrophoretic mobility of the 85-kDa PLA2, as determined by Western blot analysis, suggesting that phosphorylation of the 85-kDa PLA2 likely underlies its increase in catalytic activity. Although stimulation of neutrophils with individual lipoxygenase metabolites did not induce significant mobilization of endogenous AA, they greatly enhanced the N- formylmethiony-leucyl-phenylalanine-induced mobilization of AA as determined by mass spectrometry analysis. Our findings support a positive-feedback model in which stimulus-induced release of AA or exocytosis of secretory PLA2 modulate the activity of the cytosolic 85-kDa PLA2 by initiating the formation of LTB4. The nascent LTB4 is then released to act on the LTB4 receptor and thereby promote further activation of the 85-kDa PLA2. Since 5- HETE and LTB4 are known to prime the synthesis of platelet-activating factor, the findings suggest that 85-kDa PLA2 plays a role in platelet- activating factor synthesis.

Authors
Wijkander, J; O'Flaherty, JT; Nixon, AB; Wykle, RL
MLA Citation
Wijkander, J, O'Flaherty, JT, Nixon, AB, and Wykle, RL. "5-Lipoxygenase products modulate the activity of the 85-kDa phospholipase A2 in human neutrophils." Journal of Biological Chemistry 270.44 (1995): 26543-26549.
PMID
7592874
Source
scival
Published In
Journal of Biological Chemistry
Volume
270
Issue
44
Publish Date
1995
Start Page
26543
End Page
26549
DOI
10.1074/jbc.270.44.26543

Effects of CoA-independent transacylase inhibitors on the production of lipid inflammatory mediators

The enzyme CoA-independent transacylase (CoA-IT) has been proposed to mediate the movement of arachidonate between specific phospholipid subclasses, and we have shown that two inhibitors of CoA-IT (SK and F 98625 and SK and F 45905) block this movement. In this report, we use these inhibitors to further characterize the role of CoA-IT in the production of lipid mediators. SK and F 98625 (diethyl 7-(3,4,5-triphenyl-2-oxo-2,3- dihydro-imidazol-1-yl)heptane-phosphonate) and SK and F 45905 (2[2-[3-(4- chloro-3-trifluoromethylphenyl)ureido]-4-trifluoromethyl phenoxy]-4,5- dichlorobenzenesulfonic acid) inhibited CoA-IT activity (IC50 values of 9 μM and 6 μM, respectively). Neither compound had any effect on cyclooxygenase, 14-kDa PLA2 or acetyltransferase activities at concentrations below 20 μM. However, SK and F 45905 inhibited 85-kDa PLA2 activity (IC50 = 3 μM), and both compounds inhibited 5-lipoxygenase activity (IC50 values of 2-4 μM). In ionophore-stimulated neutrophils, SK and F 98625 and SK and F 45905 blocked the liberation of arachidonic acid from phospholipids, which suggests that the movement of arachidonate into specific phospholipid pools is a prerequisite for release. Both compounds also inhibited the production of platelet-activating factor in ionophore- stimulated neutrophils and antigen-stimulated mast cells. This inhibition of platelet-activating factor and arachidonic acid release was not mimicked by an inhibitor of 5-lipoxygenase, zileuton, which indicates that the primary mode of action of SK and F 98625 and SK and F 45905 is via inhibition of CoA- IT. SK and F 98625 and SK and F 45905 were able to decrease prostaglandin production in several inflammatory cells and to block signs of inflammation in ears of phorbol ester-challenged mice. Taken together, these results show that blockade of CoA-IT, which leads to inhibition of arachidonate remodeling between phospholipids, results in the attenuation of platelet-activating factor production, arachidonic acid release and the formation of eicosanoid products.

Authors
Winkler, JD; Fonteh, AN; Sung, C-M; Heravi, JD; Nixon, AB; Chabot-Fletcher, M; Griswold, D; Marshall, LA; Chilton, FH
MLA Citation
Winkler, JD, Fonteh, AN, Sung, C-M, Heravi, JD, Nixon, AB, Chabot-Fletcher, M, Griswold, D, Marshall, LA, and Chilton, FH. "Effects of CoA-independent transacylase inhibitors on the production of lipid inflammatory mediators." Journal of Pharmacology and Experimental Therapeutics 274.3 (1995): 1338-1347.
PMID
7562506
Source
scival
Published In
Journal of Pharmacology and Experimental Therapeutics
Volume
274
Issue
3
Publish Date
1995
Start Page
1338
End Page
1347

Evaluation of phospholipase C and D activity in stimulated human neutrophils using a phosphono analog of choline phosphoglyceride

A phosphono analog of choline phosphoglyceride was used to examine the relative contributions of phospholipase C and D in the generation of diglycerides in fMLP- and A23187-stimulated human neutrophils. The phosphono analog, 1-O-[3H]alkyl-2-lyso-sn-glycero-3-phosphonocholine, contains a carbon-phosphorus bond adjacent to the base moiety and is resistant to phospholipase D hydrolysis, while remaining susceptible to phospholipase C hydrolysis. fMLP stimulated the production of [3H]phosphatidic acid and subsequently [3H]diglyceride from cells containing 1-O-[3H]alkyl-2-acyl-sn-glycero-3-phosphocholine, but not from cells prelabeled with the phosphono analog. Treatment with A23187 also resulted in the formation of these products from cells containing 1-O-[3H]alkyl-2-acyl-sn-glycero-3-phosphocholine. Additionally, A23187 stimulated the conversion of the phosphono analog to phosphodiester-containing choline phosphoglyceride which then resulted in the generation of [3H]phosphatidic acid and subsequently [3H]diglyceride. This study demonstrates the use of a phosphono analog in assessing phospholipase C and D activity in cells and provides evidence that in fMLP- and A23187-stimulated human neutrophils, diglyceride is generated indirectly from choline phosphoglycerides by the combined activities of phospholipase D and phosphatidate phosphohydrolase. © 1993.

Authors
Strum, JC; Nixon, AB; Daniel, LW; Wykle, RL
MLA Citation
Strum, JC, Nixon, AB, Daniel, LW, and Wykle, RL. "Evaluation of phospholipase C and D activity in stimulated human neutrophils using a phosphono analog of choline phosphoglyceride." Biochimica et Biophysica Acta (BBA)/Lipids and Lipid Metabolism 1169.1 (1993): 25-29.
PMID
8334146
Source
scival
Published In
BBA - Lipids and Lipid Metabolism
Volume
1169
Issue
1
Publish Date
1993
Start Page
25
End Page
29
DOI
10.1016/0005-2760(93)90077-M

A facile synthesis of 1-O-alkyl-2-(R)-hydroxypropane-3-phosphonocholine (lyso-phosphono-platelet activating factor)

The synthesis of 1-O-alkyl-2-(R)-hydroxypropane-3-phosphonocholine is described. An efficient alkylation procedure using (NaH/DMSO) catalysis is also described and applied to the synthetic scheme. The key intermediate 1-O-alkyl-2-(R)-O-benzyl-3-bromopropane was phosphonylated using tris(trimethylsilyl)phosphite; the resulting phophonic acid was coupled to choline using trichloroacetonitrile/pyridine or triisopropylbenzenesulfonyl chloride/pyridine followed by catalytic hydrogenation to yield 1-O-alkyl-2(R)-hydroxypropane-3-phosphonocholine. © 1992.

Authors
Schmitt, JD; Nixon, AB; Emilsson, A; Daniel, LW; Wykle, RL
MLA Citation
Schmitt, JD, Nixon, AB, Emilsson, A, Daniel, LW, and Wykle, RL. "A facile synthesis of 1-O-alkyl-2-(R)-hydroxypropane-3-phosphonocholine (lyso-phosphono-platelet activating factor)." Chemistry and Physics of Lipids 62.3 (1992): 263-268.
PMID
1468125
Source
scival
Published In
Chemistry and Physics of Lipids
Volume
62
Issue
3
Publish Date
1992
Start Page
263
End Page
268
DOI
10.1016/0009-3084(92)90063-U
Show More