Glioblastoma Multiforme (GBM) tumors are the third leading cause of cancer-related death among adults aged 30 - 50 years, even though they account for less than 1.5% of all new cancer cases reported in the United States each year. The very high mortality rate of GBMs (>90% at 2 years) has remained relatively unchanged over the past 40 years despite aggressive therapy that includes surgical resection, radiotherapy and chemotherapy. However, a clear survival advantage of post-resection radiation has been established by randomized trials, showing that the median survival of GBM patients was improved, from approximately 6 months to 10-12 months, following near-maximal brain-tolerated doses of ionizing radiation. The central role that radiation plays in treating GBM is also illustrated by the landmark Stupp study showing that concurrent radiation and Temozolomide can further increase median survival from 12.1 to 14.6 months. Thus, radiation remains the mainstay of GBM therapy, and the success of the Stupp study, though modest, offers hope that radiotherapy of GBMs can be further improved. Any improvement in therapy would require a more mechanistic understanding of the basis of GBM radioresistance. The lack of improvement in GBM treatment is partly due to a paucity of appropriate genetic models that can be used to delineate the effects of genetic changes that occur in GBMs on radioresistance. The recent mapping of the GBM genome by the Cancer Genome Atlas Network revealed that these tumors have radically altered genomes with many mutations, gene copy number gains and losses, and methylation changes. Amongst the myriad genetic alterations that populate the GBM genomic landscape, 5 key genetic alterations dominate: loss of Ink4a, Arf, p53, or PTEN and amplification of EGFR (especially, the constitutively active EGFRvIII). Which of these key genetic aberrations may confer therapeutic resistance remains unclear. Understanding the contribution of these lesions, singly and in combination, to GBM radioresistance along with the underlying mechanism(s) will be of paramount importance in developing more effective therapeutic modalities. Towards this goal, we plan to use conditional knock out mouse models wherein these key genetic lesions can be introduced in astrocytes and neural stem cells (NSCs) both in culture and in the mouse brain using the Cre-ERT2 system. We propose to examine how these genetic changes impact on mechanisms for the repair of radiation-induced DNA double-strand breaks (DSBs). Based upon our preliminary results, we hypothesize that cross talk between the EGFRvIII-PI3K-Akt axis and the DNA repair enzyme, DNA-PKcs, underlies the radioresistance of GBMs and that this connection can be targeted for effective radiotherapy. Specifically, we propose: 1. To confirm that GBM radioresistance is conferred by interactions between key GBM-specific genetic lesions. 2. To validate that phosphorylation of DNA-PKcs by Akt promotes the repair of radiation-induced DNA breaks. 3. To test whether Akt-DNA-PKcs is a vulnerable node that can be targeted to improve radiotherapy of GBMs.

Public Health Relevance

Glioblastoma multiforme is the most common and aggressive primary brain tumor in adults and is universally fatal despite aggressive treatment regimens including surgical resection, chemotherapy, and radiotherapy. We propose to understand the basis of radioresistance in glioblastomas and postulate that this is due to proficient repair of radiation-induced DNA damage due to activation of specific signaling pathways by GBM-relevant genetic changes. This would help to identify vulnerable nodes that could be targeted for effective radiosensitization of these tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA149461-04
Application #
8605809
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Ahmed, Mansoor M
Project Start
2011-01-01
Project End
2015-12-31
Budget Start
2014-01-29
Budget End
2014-12-31
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Gong, Ke; Guo, Gao; Gerber, David E et al. (2018) TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer. J Clin Invest 128:2500-2518
Li, Xiangyi; Baek, GuemHee; Ramanand, Susmita G et al. (2018) BRD4 Promotes DNA Repair and Mediates the Formation of TMPRSS2-ERG Gene Rearrangements in Prostate Cancer. Cell Rep 22:796-808
Yin, Yi; Li, Rui; Xu, Kangling et al. (2017) Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation. Cancer Res 77:4745-4754
Tomimatsu, Nozomi; Mukherjee, Bipasha; Harris, Janelle Louise et al. (2017) DNA-damage-induced degradation of EXO1 exonuclease limits DNA end resection to ensure accurate DNA repair. J Biol Chem 292:10779-10790
Todorova, Pavlina Krasimirova; Mukherjee, Bipasha; Burma, Sandeep (2017) MET signaling promotes DNA repair and radiation resistance in glioblastoma stem-like cells. Ann Transl Med 5:61
Saki, Mohammad; Makino, Haruhiko; Javvadi, Prashanthi et al. (2017) EGFR Mutations Compromise Hypoxia-Associated Radiation Resistance through Impaired Replication Fork-Associated DNA Damage Repair. Mol Cancer Res 15:1503-1516
Kim, Hyun-Suk; Nickoloff, Jac A; Wu, Yuehan et al. (2017) Endonuclease EEPD1 Is a Gatekeeper for Repair of Stressed Replication Forks. J Biol Chem 292:2795-2804
Kalimutho, Murugan; Bain, Amanda L; Mukherjee, Bipasha et al. (2017) Enhanced dependency of KRAS-mutant colorectal cancer cells on RAD51-dependent homologous recombination repair identified from genetic interactions in Saccharomyces cerevisiae. Mol Oncol 11:470-490
Guo, Gao; Gong, Ke; Ali, Sonia et al. (2017) A TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma. Nat Neurosci 20:1074-1084
Gil Del Alcazar, Carlos Rodrigo; Todorova, Pavlina Krasimirova; Habib, Amyn A et al. (2016) Augmented HR Repair Mediates Acquired Temozolomide Resistance in Glioblastoma. Mol Cancer Res 14:928-940

Showing the most recent 10 out of 29 publications