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Grant Details

Grant Number: 5R01CA127716-05 Interpret this number
Primary Investigator: Sarkaria, Jann
Organization: Mayo Clinic Rochester
Project Title: Epigenetic Regulation of Temozolomide Responsiveness in Glioblastoma
Fiscal Year: 2012


Abstract

DESCRIPTION (provided by applicant): Temozolomide (TMZ) combined with radiation therapy is the standard of care for newly diagnosed patients with glioblastoma multiforme (GBM). A key cytotoxic lesion induced by TMZ is repaired by the O6- methylguanine-methyltransferase (MGMT) DNA repair protein, and disruption of MGMT activity significantly increases the sensitivity of tumors to TMZ. Thus, understanding the regulatory mechanisms controlling MGMT activity is of critical clinical importance. An aspect of this regulation that is of fundamental significance involves MGMT methylation, and several studies have demonstrated an association between MGMT promoter methylation and improved GBM patient survival. However, the methylation specific PCR (MS-PCR) reaction that is used most often to interpret MGMT promoter methylation status examines only 9 of 98 potential CpG methylation sites. Because changes in MGMT promoter methylation outside of the region evaluated by MS-PCR can dramatically affect MGMT expression, we hypothesize that a comprehensive evaluation of CpG island methylation will provide a more robust predictor of TMZ response. To further study the influence of MGMT methylation on TMZ sensitivity, the survival benefit of TMZ therapy has been evaluated in an intracranial xenograft therapy model using a panel of 17 human GBMs that were established and maintained by serial passage in the flank of nude mice. Our preliminary data suggest that methylation at 4 MGMT promoter CpG sites, which are not queried by the routinely-used MGMT MS-PCR analysis, is a more accurate predictor of individual tumor TMZ responsiveness. The primary objective of the studies associated with this application is to conclusively address the relationship between GBM response to TMZ and MGMT methylation by identifying the CpG methylation sites that are critical to regulating MGMT expression. For this purpose, the following experimental plan is put forward. In aim 1, key CpG methylation sites predictive of survival will be identified using GBM tumor specimens from patients treated with TMZ + radiation on 3 prospective clinical trials. In aim 2, the influence of MGMT methylation patterns on TMZ sensitivity and MGMT mRNA and protein expression will be evaluated our panel of GBM xenografts that collectively recapitulate the range of TMZ responses observed in patient clinical trials. Aim 3 studies will focus on the use of xenografts for investigating relationships between changes in MGMT CpG methylation patterns and acquired resistance to therapy, which has been observed in association with our preliminary xenograft investigations. In total, this study plan will provide a definitive delineation of MGMT CpG methylation patterns that consistently and reliably predict tumor response to TMZ therapy, and will address the role of changes to MGMT CpG methylation in acquired resistance to TMZ. The addition of temozolomide to standard radiation therapy significantly prolongs survival in a subset of patients with glioblastoma multiforme, which is the most lethal form of brain cancer. The studies planned are designed to develop a robust predictor of temozolomide responsiveness in patients that could be used to customize therapy for patients with this disease. Investigations into the mechanism of temozolomide drug resistance also will provide the foundation for future development of novel temozolomide sensitizing strategies to further improve the cure rate for patients with glioblastoma multiforme



Publications

Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit.
Authors: Oliva C.R. , Zhang W. , Langford C. , Suto M.J. , Griguer C.E. .
Source: Oncotarget, 2017-06-06; 8(23), p. 37568-37583.
PMID: 28455961
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Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System.
Authors: Parrish K.E. , Cen L. , Murray J. , Calligaris D. , Kizilbash S. , Mittapalli R.K. , Carlson B.L. , Schroeder M.A. , Sludden J. , Boddy A.V. , et al. .
Source: Molecular cancer therapeutics, 2015 Dec; 14(12), p. 2735-43.
EPub date: 2015-10-05.
PMID: 26438157
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Nuclear-encoded cytochrome c oxidase subunit 4 regulates BMI1 expression and determines proliferative capacity of high-grade gliomas.
Authors: Oliva C.R. , Markert T. , Gillespie G.Y. , Griguer C.E. .
Source: Oncotarget, 2015-02-28; 6(6), p. 4330-44.
PMID: 25726526
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Discordant in vitro and in vivo chemopotentiating effects of the PARP inhibitor veliparib in temozolomide-sensitive versus -resistant glioblastoma multiforme xenografts.
Authors: Gupta S.K. , Mladek A.C. , Carlson B.L. , Boakye-Agyeman F. , Bakken K.K. , Kizilbash S.H. , Schroeder M.A. , Reid J. , Sarkaria J.N. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2014-07-15; 20(14), p. 3730-41.
EPub date: 2014-05-16.
PMID: 24838527
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Efficacy of protracted temozolomide dosing is limited in MGMT unmethylated GBM xenograft models.
Authors: Cen L. , Carlson B.L. , Pokorny J.L. , Mladek A.C. , Grogan P.T. , Schroeder M.A. , Decker P.A. , Anderson S.K. , Giannini C. , Wu W. , et al. .
Source: Neuro-oncology, 2013 Jun; 15(6), p. 735-46.
EPub date: 2013-03-10.
PMID: 23479134
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ATM inhibitor KU-55933 increases the TMZ responsiveness of only inherently TMZ sensitive GBM cells.
Authors: Nadkarni A. , Shrivastav M. , Mladek A.C. , Schwingler P.M. , Grogan P.T. , Chen J. , Sarkaria J.N. .
Source: Journal of neuro-oncology, 2012 Dec; 110(3), p. 349-57.
EPub date: 2012-10-03.
PMID: 23054561
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Inhibition of histone deacetylation potentiates the evolution of acquired temozolomide resistance linked to MGMT upregulation in glioblastoma xenografts.
Authors: Kitange G.J. , Mladek A.C. , Carlson B.L. , Schroeder M.A. , Pokorny J.L. , Cen L. , Decker P.A. , Wu W. , Lomberk G.A. , Gupta S.K. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2012-08-01; 18(15), p. 4070-9.
EPub date: 2012-06-06.
PMID: 22675172
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Establishment, maintenance and in vitro and in vivo applications of primary human glioblastoma multiforme (GBM) xenograft models for translational biology studies and drug discovery.
Authors: Carlson B.L. , Pokorny J.L. , Schroeder M.A. , Sarkaria J.N. .
Source: Current protocols in pharmacology, 2011 Mar; Chapter 14, p. Unit 14.16.
PMID: 21743824
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Acquisition of temozolomide chemoresistance in gliomas leads to remodeling of mitochondrial electron transport chain.
Authors: Oliva C.R. , Nozell S.E. , Diers A. , McClugage S.G. , Sarkaria J.N. , Markert J.M. , Darley-Usmar V.M. , Bailey S.M. , Gillespie G.Y. , Landar A. , et al. .
Source: The Journal of biological chemistry, 2010-12-17; 285(51), p. 39759-67.
EPub date: 2010-09-24.
PMID: 20870728
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Expression of CD74 in high grade gliomas: a potential role in temozolomide resistance.
Authors: Kitange G.J. , Carlson B.L. , Schroeder M.A. , Decker P.A. , Morlan B.W. , Wu W. , Ballman K.V. , Giannini C. , Sarkaria J.N. .
Source: Journal of neuro-oncology, 2010 Nov; 100(2), p. 177-86.
EPub date: 2010-05-05.
PMID: 20443131
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ZD6474, a multitargeted inhibitor for receptor tyrosine kinases, suppresses growth of gliomas expressing an epidermal growth factor receptor mutant, EGFRvIII, in the brain.
Authors: Yiin J.J. , Hu B. , Schornack P.A. , Sengar R.S. , Liu K.W. , Feng H. , Lieberman F.S. , Chiou S.H. , Sarkaria J.N. , Wiener E.C. , et al. .
Source: Molecular cancer therapeutics, 2010 Apr; 9(4), p. 929-41.
EPub date: 2010-04-06.
PMID: 20371720
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Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1.
Authors: Verhaak R.G. , Hoadley K.A. , Purdom E. , Wang V. , Qi Y. , Wilkerson M.D. , Miller C.R. , Ding L. , Golub T. , Mesirov J.P. , et al. .
Source: Cancer cell, 2010-01-19; 17(1), p. 98-110.
PMID: 20129251
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Radiosensitizing effects of temozolomide observed in vivo only in a subset of O6-methylguanine-DNA methyltransferase methylated glioblastoma multiforme xenografts.
Authors: Carlson B.L. , Grogan P.T. , Mladek A.C. , Schroeder M.A. , Kitange G.J. , Decker P.A. , Giannini C. , Wu W. , Ballman K.A. , James C.D. , et al. .
Source: International journal of radiation oncology, biology, physics, 2009-09-01; 75(1), p. 212-9.
PMID: 19695438
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Induction of MGMT expression is associated with temozolomide resistance in glioblastoma xenografts.
Authors: Kitange G.J. , Carlson B.L. , Schroeder M.A. , Grogan P.T. , Lamont J.D. , Decker P.A. , Wu W. , James C.D. , Sarkaria J.N. .
Source: Neuro-oncology, 2009 Jun; 11(3), p. 281-91.
EPub date: 2008-10-24.
PMID: 18952979
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Evaluation of MGMT promoter methylation status and correlation with temozolomide response in orthotopic glioblastoma xenograft model.
Authors: Kitange G.J. , Carlson B.L. , Mladek A.C. , Decker P.A. , Schroeder M.A. , Wu W. , Grogan P.T. , Giannini C. , Ballman K.V. , Buckner J.C. , et al. .
Source: Journal of neuro-oncology, 2009 Mar; 92(1), p. 23-31.
EPub date: 2008-11-15.
PMID: 19011762
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Effective sensitization of temozolomide by ABT-888 is lost with development of temozolomide resistance in glioblastoma xenograft lines.
Authors: Clarke M.J. , Mulligan E.A. , Grogan P.T. , Mladek A.C. , Carlson B.L. , Schroeder M.A. , Curtin N.J. , Lou Z. , Decker P.A. , Wu W. , et al. .
Source: Molecular cancer therapeutics, 2009 Feb; 8(2), p. 407-14.
EPub date: 2009-01-27.
PMID: 19174557
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p53 Small-molecule inhibitor enhances temozolomide cytotoxic activity against intracranial glioblastoma xenografts.
Authors: Dinca E.B. , Lu K.V. , Sarkaria J.N. , Pieper R.O. , Prados M.D. , Haas-Kogan D.A. , Vandenberg S.R. , Berger M.S. , James C.D. .
Source: Cancer research, 2008-12-15; 68(24), p. 10034-9.
PMID: 19074867
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Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177.
Authors: Brown P.D. , Krishnan S. , Sarkaria J.N. , Wu W. , Jaeckle K.A. , Uhm J.H. , Geoffroy F.J. , Arusell R. , Kitange G. , Jenkins R.B. , et al. .
Source: Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2008-12-01; 26(34), p. 5603-9.
EPub date: 2008-10-27.
PMID: 18955445
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Mechanisms of chemoresistance to alkylating agents in malignant glioma.
Authors: Sarkaria J.N. , Kitange G.J. , James C.D. , Plummer R. , Calvert H. , Weller M. , Wick W. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2008-05-15; 14(10), p. 2900-8.
PMID: 18483356
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Bioluminescence monitoring of intracranial glioblastoma xenograft: response to primary and salvage temozolomide therapy.
Authors: Dinca E.B. , Sarkaria J.N. , Schroeder M.A. , Carlson B.L. , Voicu R. , Gupta N. , Berger M.S. , James C.D. .
Source: Journal of neurosurgery, 2007 Sep; 107(3), p. 610-6.
PMID: 17886562
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