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

Research output: Contribution to journalArticle

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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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temozolomide
Methyltransferases
Glioblastoma
Biomarkers
Heterografts
DNA
Methylation
Therapeutics
DNA Repair
DNA Damage
Polymerase Chain Reaction
Survival
veliparib
Genes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma. / Gupta, Shiv K.; Kizilbash, Sani; Carlson, Brett L.; Mladek, Ann C.; Boakye-Agyeman, Felix; Bakken, Katrina K.; Pokorny, Jenny L.; Schroeder, Mark A.; Decker, Paul A.; Cen, Ling; Eckel-Passow, Jeanette E; Sarkar, Gobinda; Ballman, Karla V.; Reid, Joel M; Jenkins, Robert Brian; Verhaak, Roeland G.; Sulman, Erik P.; Kitange, Gaspar J.; Sarkaria, Jann N.

In: Journal of the National Cancer Institute, Vol. 108, No. 5, djv369, 01.05.2016.

Research output: Contribution to journalArticle

Gupta, SK, Kizilbash, S, Carlson, BL, Mladek, AC, Boakye-Agyeman, F, Bakken, KK, Pokorny, JL, Schroeder, MA, Decker, PA, Cen, L, Eckel-Passow, JE, Sarkar, G, Ballman, KV, Reid, JM, Jenkins, RB, Verhaak, RG, Sulman, EP, Kitange, GJ & Sarkaria, JN 2016, 'Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma', Journal of the National Cancer Institute, vol. 108, no. 5, djv369. https://doi.org/10.1093/jnci/djv369
Gupta, Shiv K. ; Kizilbash, Sani ; Carlson, Brett L. ; Mladek, Ann C. ; Boakye-Agyeman, Felix ; Bakken, Katrina K. ; Pokorny, Jenny L. ; Schroeder, Mark A. ; Decker, Paul A. ; Cen, Ling ; Eckel-Passow, Jeanette E ; Sarkar, Gobinda ; Ballman, Karla V. ; Reid, Joel M ; Jenkins, Robert Brian ; Verhaak, Roeland G. ; Sulman, Erik P. ; Kitange, Gaspar J. ; Sarkaria, Jann N. / Delineation of MGMT Hypermethylation as a Biomarker for Veliparib-Mediated Temozolomide-Sensitizing Therapy of Glioblastoma. In: Journal of the National Cancer Institute. 2016 ; Vol. 108, No. 5.
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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",
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AU - Kizilbash, Sani

AU - Carlson, Brett L.

AU - Mladek, Ann C.

AU - Boakye-Agyeman, Felix

AU - Bakken, Katrina K.

AU - Pokorny, Jenny L.

AU - Schroeder, Mark A.

AU - Decker, Paul A.

AU - Cen, Ling

AU - Eckel-Passow, Jeanette E

AU - Sarkar, Gobinda

AU - Ballman, Karla V.

AU - Reid, Joel M

AU - Jenkins, Robert Brian

AU - Verhaak, Roeland G.

AU - Sulman, Erik P.

AU - Kitange, Gaspar J.

AU - Sarkaria, Jann N

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