Abstract | BACKGROUND: 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.
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Authors | 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 |
Journal | Journal of the National Cancer Institute
(J Natl Cancer Inst)
Vol. 108
Issue 5
(May 2016)
ISSN: 1460-2105 [Electronic] United States |
PMID | 26615020
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: [email protected]. |
Chemical References |
- Antineoplastic Agents, Alkylating
- Benzimidazoles
- Poly(ADP-ribose) Polymerase Inhibitors
- Tumor Suppressor Proteins
- veliparib
- Dacarbazine
- DNA Modification Methylases
- MGMT protein, human
- DNA Repair Enzymes
- Temozolomide
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Topics |
- Animals
- Antineoplastic Agents, Alkylating
(pharmacology)
- Antineoplastic Combined Chemotherapy Protocols
(pharmacology)
- Benzimidazoles
(pharmacology)
- Cell Line, Tumor
- DNA Methylation
(drug effects)
- DNA Modification Methylases
(genetics)
- DNA Repair Enzymes
(genetics)
- Dacarbazine
(analogs & derivatives, pharmacology)
- Female
- Gene Expression Regulation, Neoplastic
(drug effects)
- Glioblastoma
(drug therapy, genetics)
- Humans
- Mice
- Mice, Nude
- Poly(ADP-ribose) Polymerase Inhibitors
(pharmacology)
- Polymerase Chain Reaction
- Random Allocation
- Temozolomide
- Tumor Suppressor Proteins
(genetics)
- Up-Regulation
(drug effects)
- Xenograft Model Antitumor Assays
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