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.
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.
|Camacho, C V; Todorova, P K; Hardebeck, M C et al. (2015) DNA double-strand breaks cooperate with loss of Ink4 and Arf tumor suppressors to generate glioblastomas with frequent Met amplification. Oncogene 34:1064-72|
|Li, L; Chakraborty, S; Yang, C-R et al. (2014) An EGFR wild type-EGFRvIII-HB-EGF feed-forward loop regulates the activation of EGFRvIII. Oncogene 33:4253-64|
|Tomimatsu, Nozomi; Mukherjee, Bipasha; Catherine Hardebeck, Molly et al. (2014) Phosphorylation of EXO1 by CDKs 1 and 2 regulates DNA end resection and repair pathway choice. Nat Commun 5:3561|
|Gil del Alcazar, Carlos Rodrigo; Hardebeck, Molly Catherine; Mukherjee, Bipasha et al. (2014) Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma. Clin Cancer Res 20:1235-48|
|Chakraborty, Sharmistha; Li, Li; Tang, Hao et al. (2013) Cytoplasmic TRADD confers a worse prognosis in glioblastoma. Neoplasia 15:888-97|
|Wu, Kaijie; Xie, Daxing; Zou, Yonglong et al. (2013) The mechanism of DAB2IP in chemoresistance of prostate cancer cells. Clin Cancer Res 19:4740-9|
|Puliyappadamba, Vineshkumar Thidil; Chakraborty, Sharmistha; Chauncey, Sandili S et al. (2013) Opposing effect of EGFRWT on EGFRvIII-mediated NF-*B activation with RIP1 as a cell death switch. Cell Rep 4:764-75|
|Mukherjee, Bipasha; Tomimatsu, Nozomi; Amancherla, Kaushik et al. (2012) The dual PI3K/mTOR inhibitor NVP-BEZ235 is a potent inhibitor of ATM- and DNA-PKCs-mediated DNA damage responses. Neoplasia 14:34-43|
|Tomimatsu, Nozomi; Mukherjee, Bipasha; Deland, Katherine et al. (2012) Exo1 plays a major role in DNA end resection in humans and influences double-strand break repair and damage signaling decisions. DNA Repair (Amst) 11:441-8|
|Morris, Christelle; Tomimatsu, Nozomi; Richard, Derek J et al. (2012) INT6/EIF3E interacts with ATM and is required for proper execution of the DNA damage response in human cells. Cancer Res 72:2006-16|