Glioblastoma (GBM) patients only survive an average of 15 months. Tumor resistance to radiation and other forms therapy is the leading challenge in GBM treatment. The mechanisms underlying GBM resistance to radiation therapy (RT) remain poorly understood and agents that selectively sensitize GBM to RT while sparing normal brain tissue are lacking. Pyruvate kinase M2 (PKM2) is the key cytoplasmic glycolytic enzyme, which is critical GBM tumor cell proliferation and expresses highly in cancer cells but minimally in normal brain tissue. Our laboratory has discovered a novel signaling network which connects the nuclear PKM2 function with homologous recombination (HR)-mediated repair of DNA double-strand breaks (DSBs) and GBM tumor cell resistance to radiation-induced cytotoxicity. Furthermore, our preliminary data revealed that PKM2 accumulates in the nucleus following irradiation and interacts with the critical HR rate-limiting protein, CtlP. Meanwhile, ataxia-telangiectasia mutated (ATM), the prime DNA-damage response protein kinase, phosphorylates PKM2 and regulates radiation-induced PKM2 nuclear accumulation and PKM2-depedent HR DSB repair. Therefore, we hypothesize that, in addition to controlling cytosolic glycolytic metabolism, nuclear PKM2 responds to novel upstream regulation by ATM to dictate the fate of irradiated GBM cells by promoting the repair of radiation-induced DSBs through enhanced CtIP-directed HR. A series of in vitro and in vivo experiments are proposed to test our hypotheses:
Aim 1 will determine whether CtIP is a critical downstream functional target in PKM2-promotion of HR DSB repair and survival of irradiated GBM cells.
Aim 2 will determine how ATM regulates PKM2 in HR DSB repair and subsequent GBM cell survival following radiation treatment.
Aim 3 will determine whether targeting nuclear PKM2-dependent HR repair selectively sensitizes GBM tumor cells to DNA damage while sparing noncancerous brain cells in vitro and in vivo.

Public Health Relevance

In an effort to improve treatment outcome of glioblastoma patients, pharmacologic agents which can enhance GBM tumor response to and spare normal brain tissue from radiation treatment induced cytotoxicity have been vigorously investigated. As such, the overarching goal of this proposal is to determine the molecular mechanisms that determine the response of GBM tumor cells as well as normal brain neurons to DNA damage based radiation therapy with a goal toward improve the therapeutic index in GBM treatment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA188500-02
Application #
8920115
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
2014-09-02
Project End
2016-06-30
Budget Start
2015-09-01
Budget End
2016-06-30
Support Year
2
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Ohio State University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Yu, Hao; Harrison, Fiona Edith; Xia, Fen (2018) Altered DNA repair; an early pathogenic pathway in Alzheimer's disease and obesity. Sci Rep 8:5600
Sizemore, Steven T; Zhang, Manchao; Cho, Ju Hwan et al. (2018) Pyruvate kinase M2 regulates homologous recombination-mediated DNA double-strand break repair. Cell Res 28:1090-1102
Salamekh, Samer; Rong, Yi; Ayan, Ahmet S et al. (2016) Inter-Fraction Tumor Volume Response during Lung Stereotactic Body Radiation Therapy Correlated to Patient Variables. PLoS One 11:e0153245
Cui, Ri; Meng, Wei; Sun, Hui-Lung et al. (2015) MicroRNA-224 promotes tumor progression in nonsmall cell lung cancer. Proc Natl Acad Sci U S A 112:E4288-97
Wu, Yuehan; Lee, Suk-Hee; Williamson, Elizabeth A et al. (2015) EEPD1 Rescues Stressed Replication Forks and Maintains Genome Stability by Promoting End Resection and Homologous Recombination Repair. PLoS Genet 11:e1005675
Bell, Erica Hlavin; Kirste, Simon; Fleming, Jessica L et al. (2015) A novel miRNA-based predictive model for biochemical failure following post-prostatectomy salvage radiation therapy. PLoS One 10:e0118745
Shirai, Katsuyuki; Chakravarti, Arnab (2011) Towards personalized therapy for patients with glioblastoma. Expert Rev Anticancer Ther 11:1935-44