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- Title
Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma.
- Authors
Gupta, Shiv K.; Kizilbash, Sani H.; Carlson, Brett L.; Mladek, Ann C.; Boakye-Agyeman, Felix; Bakken, Katrina K.; Pokorny, Jenny L.; Schroeder, Mark A.; Decker, Paul A.; Ling Cen; Eckel-Passow, Jeanette E.; Sarkar, Gobinda; Ballman, Karla V.; Reid, Joel M.; Jenkins, Robert B.; Verhaak, Roeland G.; Sulman, Erik P.; Kitange, Gaspar J.; Sarkaria, Jann N.; Cen, Ling
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Subjects
ANIMAL experimentation; ANTINEOPLASTIC agents; BIOCHEMISTRY; CELL lines; DNA; ENZYMES; GENES; GLIOMAS; HETEROCYCLIC compounds; PHENOMENOLOGY; MICE; POLYMERASE chain reaction; PROTEINS; RESEARCH funding; STATISTICAL sampling; DNA methylation; DACARBAZINE; PHARMACODYNAMICS
- Publication
JNCI: Journal of the National Cancer Institute, 2016, Vol 108, Issue 5, p1
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djv369