Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma

Shiv K. Gupta, Sani H. Kizilbash, Brett L. Carlson, Ann C. Mladek, Felix Boakye-Agyeman, Katrina K. Bakken, Jenny L. Pokorny, Mark A. Schroeder, Paul A. Decker, Ling Cen, Jeanette E. Eckel-Passow, Gobinda Sarkar, Karla V. Ballman, Joel M. Reid, Robert B. Jenkins, Roeland G. Verhaak, Erik P. Sulman, Gaspar J. Kitange, Jann N. Sarkaria

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageEnglish (US)
JournalJournal of the National Cancer Institute
Volume108
Issue number5
DOIs
StatePublished - May 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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