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

Shiv K. Gupta, Sani 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 Brian Jenkins, Roeland G. Verhaak, Erik P. Sulman, Gaspar J. Kitange, Jann N Sarkaria

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31 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

Original languageEnglish (US)
Article numberdjv369
JournalJournal of the National Cancer Institute
Volume108
Issue number5
DOIs
StatePublished - May 1 2016

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Gupta, S. K., Kizilbash, S., Carlson, B. L., Mladek, A. C., Boakye-Agyeman, F., Bakken, K. K., Pokorny, J. L., Schroeder, M. A., Decker, P. A., Cen, L., Eckel-Passow, J. E., Sarkar, G., Ballman, K. V., Reid, J. M., Jenkins, R. B., Verhaak, R. G., Sulman, E. P., Kitange, G. J., & Sarkaria, J. N. (2016). Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma. Journal of the National Cancer Institute, 108(5), [djv369]. https://doi.org/10.1093/jnci/djv369