Shiv K Gupta1, Sani H Kizilbash1, Brett L Carlson1, Ann C Mladek1, Felix Boakye-Agyeman1, Katrina K Bakken1, Jenny L Pokorny1, Mark A Schroeder1, Paul A Decker1, Ling Cen1, Jeanette E Eckel-Passow1, Gobinda Sarkar1, Karla V Ballman1, Joel M Reid1, Robert B Jenkins1, Roeland G Verhaak1, Erik P Sulman1, Gaspar J Kitange1, Jann N Sarkaria2. 1. Department of Radiation Oncology (SKG, BLC, ACM, KKB, JLP, MAS, LC, GJK, JNS), Division of Medical Oncology (SHK), Molecular Pharmacology and Experimental Therapeutics (FBA, JMR), Division of Biomedical Statistics and Informatics (PAD, JEEP, KVB), and Laboratory Medicine and Pathology (GS, RBJ), Mayo Clinic, Rochester MN; The University of Texas, MD Anderson Cancer Center, Houston, TX (RGV, EPS). 2. Department of Radiation Oncology (SKG, BLC, ACM, KKB, JLP, MAS, LC, GJK, JNS), Division of Medical Oncology (SHK), Molecular Pharmacology and Experimental Therapeutics (FBA, JMR), Division of Biomedical Statistics and Informatics (PAD, JEEP, KVB), and Laboratory Medicine and Pathology (GS, RBJ), Mayo Clinic, Rochester MN; The University of Texas, MD Anderson Cancer Center, Houston, TX (RGV, EPS). sarkaria.jann@mayo.edu.
Abstract
BACKGROUND: Sensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed. METHODS: The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided. DNA damage was analyzed by γH2AX immunostaining and promoter methylation of DNA repair gene O6-methylguanine-DNA-methyltransferase (MGMT) by Clinical Laboratory Improvement Amendments-approved methylation-specific polymerase chain reaction. RESULTS: The combination of TMZ/veliparib statistically significantly extended survival of GBM models (P < .05 by log-rank) compared with TMZ alone in five of 20 MGMT-hypermethylated lines (average extension in median survival = 87 days, range = 20-150 days), while the combination was ineffective in six MGMT-unmethylated lines. In the MGMT promoter-hypermethylated GBM12 line (median survival with TMZ+veliparib = 189 days, 95% confidence interval [CI] = 59 to 289 days, vs TMZ alone = 98 days, 95% CI = 49 to 210 days, P = .04), the profound TMZ-sensitizing effect of veliparib was lost when MGMT was overexpressed (median survival with TMZ+veliparib = 36 days, 95% CI = 28 to 38 days, vs TMZ alone = 35 days, 95% CI = 32 to 37 days, P = .87), and a similar association was observed in two nearly isogenic GBM28 sublines with an intact vs deleted MGMT locus. In comparing DNA damage signaling after dosing with veliparib/TMZ or TMZ alone, increased phosphorylation of damage-responsive proteins (KAP1, Chk1, Chk2, and H2AX) was observed only in MGMT promoter-hypermethylated lines. CONCLUSION: Veliparib statistically significantly enhances (P < .001) the efficacy of TMZ in tumors with MGMT promoter hypermethylation. Based on these data, MGMT promoter hypermethylation is being used as an eligibility criterion for A071102 (NCT02152982), the phase II/III clinical trial evaluating TMZ/veliparib combination in patients with GBM.
BACKGROUND: Sensitizing effects of poly-ADP-ribose polymerase inhibitors have been studied in several preclinical models, but a clear understanding of predictive biomarkers is lacking. In this study, in vivo efficacy of veliparib combined with temozolomide (TMZ) was evaluated in a large panel of glioblastoma multiforme (GBM) patient-derived xenografts (PDX) and potential biomarkers were analyzed. METHODS: The efficacy of TMZ alone vs TMZ/veliparib was compared in a panel of 28 GBM PDX lines grown as orthotopic xenografts (8-10 mice per group); all tests of statistical significance were two-sided. DNA damage was analyzed by γH2AX immunostaining and promoter methylation of DNA repair gene O6-methylguanine-DNA-methyltransferase (MGMT) by Clinical Laboratory Improvement Amendments-approved methylation-specific polymerase chain reaction. RESULTS: The combination of TMZ/veliparib statistically significantly extended survival of GBM models (P < .05 by log-rank) compared with TMZ alone in five of 20 MGMT-hypermethylated lines (average extension in median survival = 87 days, range = 20-150 days), while the combination was ineffective in six MGMT-unmethylated lines. In the MGMT promoter-hypermethylated GBM12 line (median survival with TMZ+veliparib = 189 days, 95% confidence interval [CI] = 59 to 289 days, vs TMZ alone = 98 days, 95% CI = 49 to 210 days, P = .04), the profound TMZ-sensitizing effect of veliparib was lost when MGMT was overexpressed (median survival with TMZ+veliparib = 36 days, 95% CI = 28 to 38 days, vs TMZ alone = 35 days, 95% CI = 32 to 37 days, P = .87), and a similar association was observed in two nearly isogenic GBM28 sublines with an intact vs deleted MGMT locus. In comparing DNA damage signaling after dosing with veliparib/TMZ or TMZ alone, increased phosphorylation of damage-responsive proteins (KAP1, Chk1, Chk2, and H2AX) was observed only in MGMT promoter-hypermethylated lines. CONCLUSION:Veliparib statistically significantly enhances (P < .001) the efficacy of TMZ in tumors with MGMT promoter hypermethylation. Based on these data, MGMT promoter hypermethylation is being used as an eligibility criterion for A071102 (NCT02152982), the phase II/III clinical trial evaluating TMZ/veliparib combination in patients with GBM.
Authors: Sagar Agarwal; Pooja Manchanda; Michael A Vogelbaum; John R Ohlfest; William F Elmquist Journal: Drug Metab Dispos Date: 2012-09-26 Impact factor: 3.922
Authors: Gaspar J Kitange; Ann C Mladek; Brett L Carlson; Mark A Schroeder; Jenny L Pokorny; Ling Cen; Paul A Decker; Wenting Wu; Gwen A Lomberk; Shiv K Gupta; Raul A Urrutia; Jann N Sarkaria Journal: Clin Cancer Res Date: 2012-06-06 Impact factor: 12.531
Authors: Joann P Palma; Yi-Chun Wang; Luis E Rodriguez; Debra Montgomery; Paul A Ellis; Gail Bukofzer; Amanda Niquette; Xuesong Liu; Yan Shi; Loren Lasko; Gui-Dong Zhu; Thomas D Penning; Vincent L Giranda; Saul H Rosenberg; David J Frost; Cherrie K Donawho Journal: Clin Cancer Res Date: 2009-11-24 Impact factor: 12.531
Authors: Andrea Bertotti; Giorgia Migliardi; Francesco Galimi; Francesco Sassi; Davide Torti; Claudio Isella; Davide Corà; Federica Di Nicolantonio; Michela Buscarino; Consalvo Petti; Dario Ribero; Nadia Russolillo; Andrea Muratore; Paolo Massucco; Alberto Pisacane; Luca Molinaro; Emanuele Valtorta; Andrea Sartore-Bianchi; Mauro Risio; Lorenzo Capussotti; Marcello Gambacorta; Salvatore Siena; Enzo Medico; Anna Sapino; Silvia Marsoni; Paolo M Comoglio; Alberto Bardelli; Livio Trusolino Journal: Cancer Discov Date: 2011-09-02 Impact factor: 39.397
Authors: Wolfgang Wick; Michael Platten; Christoph Meisner; Jörg Felsberg; Ghazaleh Tabatabai; Matthias Simon; Guido Nikkhah; Kirsten Papsdorf; Joachim P Steinbach; Michael Sabel; Stephanie E Combs; Jan Vesper; Christian Braun; Jürgen Meixensberger; Ralf Ketter; Regine Mayer-Steinacker; Guido Reifenberger; Michael Weller Journal: Lancet Oncol Date: 2012-05-10 Impact factor: 41.316
Authors: Lara Barazzuol; Raj Jena; Neil G Burnet; Lisiane B Meira; Jonathan C G Jeynes; Karen J Kirkby; Norman F Kirkby Journal: Radiat Oncol Date: 2013-03-19 Impact factor: 3.481
Authors: Patrick Y Wen; Michael Weller; Eudocia Quant Lee; Brian M Alexander; Jill S Barnholtz-Sloan; Floris P Barthel; Tracy T Batchelor; Ranjit S Bindra; Susan M Chang; E Antonio Chiocca; Timothy F Cloughesy; John F DeGroot; Evanthia Galanis; Mark R Gilbert; Monika E Hegi; Craig Horbinski; Raymond Y Huang; Andrew B Lassman; Emilie Le Rhun; Michael Lim; Minesh P Mehta; Ingo K Mellinghoff; Giuseppe Minniti; David Nathanson; Michael Platten; Matthias Preusser; Patrick Roth; Marc Sanson; David Schiff; Susan C Short; Martin J B Taphoorn; Joerg-Christian Tonn; Jonathan Tsang; Roel G W Verhaak; Andreas von Deimling; Wolfgang Wick; Gelareh Zadeh; David A Reardon; Kenneth D Aldape; Martin J van den Bent Journal: Neuro Oncol Date: 2020-08-17 Impact factor: 12.300
Authors: Rachael A Vaubel; Shulan Tian; Dioval Remonde; Mark A Schroeder; Ann C Mladek; Gaspar J Kitange; Alissa Caron; Thomas M Kollmeyer; Rebecca Grove; Sen Peng; Brett L Carlson; Daniel J Ma; Gobinda Sarkar; Lisa Evers; Paul A Decker; Huihuang Yan; Harshil D Dhruv; Michael E Berens; Qianghu Wang; Bianca M Marin; Eric W Klee; Andrea Califano; Daniel H LaChance; Jeanette E Eckel-Passow; Roel G Verhaak; Erik P Sulman; Terry C Burns; Fredrick B Meyer; Brian P O'Neill; Nhan L Tran; Caterina Giannini; Robert B Jenkins; Ian F Parney; Jann N Sarkaria Journal: Clin Cancer Res Date: 2019-12-18 Impact factor: 12.531
Authors: Patricia A Baxter; Jack M Su; Arzu Onar-Thomas; Catherine A Billups; Xiao-Nan Li; Tina Young Poussaint; Edward R Smith; Patrick Thompson; Adekunle Adesina; Pete Ansell; Vincent Giranda; Arnold Paulino; Lindsey Kilburn; Ibrahim Quaddoumi; Alberto Broniscer; Susan M Blaney; Ira J Dunkel; Maryam Fouladi Journal: Neuro Oncol Date: 2020-06-09 Impact factor: 12.300
Authors: Sani H Kizilbash; Shiv K Gupta; Kenneth Chang; Ryo Kawashima; Karen E Parrish; Brett L Carlson; Katrina K Bakken; Ann C Mladek; Mark A Schroeder; Paul A Decker; Gaspar J Kitange; Yuqiao Shen; Ying Feng; Andrew A Protter; William F Elmquist; Jann N Sarkaria Journal: Mol Cancer Ther Date: 2017-09-25 Impact factor: 6.261
Authors: Steven T Sizemore; Rahman Mohammad; Gina M Sizemore; Somaira Nowsheen; Hao Yu; Michael C Ostrowski; Arnab Chakravarti; Fen Xia Journal: Mol Cancer Res Date: 2018-03-28 Impact factor: 5.852
Authors: Chiaki T Ishida; Yiru Zhang; Elena Bianchetti; Chang Shu; Trang T T Nguyen; Giulio Kleiner; Maria J Sanchez-Quintero; Catarina M Quinzii; Mike-Andrew Westhoff; Georg Karpel-Massler; Varun V Prabhu; Joshua E Allen; Markus D Siegelin Journal: Clin Cancer Res Date: 2018-07-23 Impact factor: 12.531
Authors: Yiru Zhang; Chiaki Tsuge Ishida; Wataru Ishida; Sheng-Fu L Lo; Junfei Zhao; Chang Shu; Elena Bianchetti; Giulio Kleiner; Maria J Sanchez-Quintero; Catarina M Quinzii; Mike-Andrew Westhoff; Georg Karpel-Massler; Peter Canoll; Markus D Siegelin Journal: Clin Cancer Res Date: 2018-05-15 Impact factor: 12.531