Glioblastoma is the most common and most malignant of human brain tumors. Recent therapeutic advances have improved control of primary tumors, with a significant fraction of tumors responding to initial therapies. Unfortunately, all glioblastomas recur and lead to patient death. For this reason, the present proposal focuses on the crucial issue of recurrent glioblastoma-with studies extending from biomarker generation and evaluation, to understanding mechanisms of therapeutic resistance, to exploration of novel therapeutic compounds. Over the past 15 years, studies supported by this grant have clarified the molecular genetic basis of glioblastomas and other malignant gliomas and have shown that the treatment of such tumors can be guided by molecular markers;in particular, the now widespread clinical use of 1p/19q testing in oligodendrogliomas emerged from studies performed under this grant. Preliminary data gathered during the last funding period have shown: glioblastomas become resistant to the effects of the alkylating agent used to treat all glioblastomas, temozolomide (TMZ), through a mechanism associated with inactivation of MSH6;MSH6-deficient glioblastomas grow more rapidly during TMZ therapy;and in vitro resources exist to evaluate defects in the TMZ-induced DNA damage response and therapeutic resistance. To address this critical issue, we propose three Specific Aims: 1) To define the spectrum of DNA repair defects that arise after TMZ therapy in glioblastoma, and to generate relevant biomarkers relating these events to clinical outcome;2) To define the mechanism whereby deficiencies in DNA damage responses enable therapeutic resistance;and 3) To define pathways that could be targeted to overcome therapeutic resistance due to defects in DNA damage response. The proposed approach will therefore extend our prior clinically relevant biomarker work to the particularly vexing problem of recurrent glioblastoma, a tumor that confounds current treatment attempts. Importantly, through continuing the work supported by this grant over the past three funding cycles, we aim to generate biomarkers and elucidate mechanisms of therapeutic resistance that could translate in the short term to changes in current diagnostic and therapeutic approaches and, in the long term, to the development of novel targeted therapies.

Public Health Relevance

The purpose of the work outlined in this proposal is to investigate defects in MSH6 and related genes/gene products that are selected for during current glioblastoma therapy and how these defects lead to therapeutic resistance and eventual patient death.
We aim to generate biomarkers and elucidate mechanisms of therapeutic resistance that could translate in the short term to changes in current diagnostic and therapeutic approaches and, in the long term, to the development of novel targeted therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA057683-20
Application #
8444318
Study Section
Cancer Biomarkers Study Section (CBSS)
Program Officer
Lively, Tracy (LUGO)
Project Start
1992-08-01
Project End
2014-02-28
Budget Start
2013-03-05
Budget End
2014-02-28
Support Year
20
Fiscal Year
2013
Total Cost
$283,710
Indirect Cost
$123,422
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Wakimoto, Hiroaki; Mohapatra, Gayatry; Kanai, Ryuichi et al. (2012) Maintenance of primary tumor phenotype and genotype in glioblastoma stem cells. Neuro Oncol 14:132-44
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Snuderl, Matija; Eichler, April F; Ligon, Keith L et al. (2009) Polysomy for chromosomes 1 and 19 predicts earlier recurrence in anaplastic oligodendrogliomas with concurrent 1p/19q loss. Clin Cancer Res 15:6430-7
Yip, Stephen; Miao, Jiangyong; Cahill, Daniel P et al. (2009) MSH6 mutations arise in glioblastomas during temozolomide therapy and mediate temozolomide resistance. Clin Cancer Res 15:4622-9

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