Glioblastoma is a major cause of cancer related death in the United States, with approximately 17,000 new cases of brain cancer diagnosed annually. Unfortunately, therapy remains inadequate and the mortality rate is high. Limited success in the treatment of glioblastoma has been demonstrated with the alkylating agent Temozolomide (TMZ). However, as with many alkylating agents, drug resistance has limited its efficacy. The base excision repair (BER) pathway provides significant resistance to TMZ by repairing greater than 80% of the TMZ-induced base lesions. As such, it is reasonable to expect that BER provides a significant level of resistance to TMZ and therefore enhanced TMZ efficacy may be obtained by blocking or interrupting repair and thereby promoting BER failure. The overall goals of this project are to utilize strategies to circumvent resistance to TMZ to enhance the cytotoxicity and potentially the efficacy of this alkylating agent. As the rate-limiting enzyme in BER, DNA polymerase ss (Polss) is important to facilitate repair and to maintain cell survival following DNA damage. Therefore, inhibition of Polss will enhance TMZ response. Specifically, we wil characterize a novel regulatory mechanism of Polss (lysine di-methylation) that can be exploited to inhibit Polss and enhance alkylating agent-induced cell death by enhancing the accumulation of cytotoxic BER intermediates (Aim 1). We posit that Polss inhibition or BER failure signals via poly(ADP)ribose (PAR) synthesis and NAD+/ATP depletion by a process that requires activation of PARP1 &PARP2 and is regulated by the enzyme PARG. We find that BER failure- induced cell death results from energy (NAD+ &ATP) depletion due to elevated PAR synthesis mediated by the PARP1/PARP2 BER sensor complex, suggesting that the response to TMZ can be enhanced via increased PAR synthesis or depletion of cellular NAD+ synthesis (Aim 2) and/or deregulation of the BER enzyme PARG (Aim 3). Overall, we will test the hypothesis that the BER pathway is a determinant of resistance to TMZ and therefore selectively targeting the BER pathway will significantly enhance TMZ efficacy. In each of our three specific aims, our goals are to identify and functionally characterize key elements of the BER pathway that control cellular responses to alkylating agents with the goal of increasing TMZ-induced cytotoxicity in cells from glioma tumors. Relevance: The proposed studies will provide new biomarkers of response to alkylation-induced DNA damage and cell death and provide insight into mechanisms that can be exploited to enhance response. Insights gained from these studies have the potential to identify novel targets for adjuvant therapies including BER inhibitors and NAD+ biosynthesis modulators that can be combined with alkylators to improve anticancer drug efficacy.
Glioblastoma is a major cause of cancer related death in the United States, with approximately 17,000 new cases of brain cancer diagnosed annually. Unfortunately, therapy remains inadequate and the mortality rate is high. Limited success in the treatment of glioblastoma has been demonstrated with the alkylating agent temozolomide (TMZ). However, as with many alkylating agents, drug resistance from active DNA repair pathways limits its efficacy. Overall, we will test the hypothesis that the base excision repair (BER) pathway is a determinant of resistance to TMZ and therefore selectively targeting critical BER pathway proteins will significantly enhance TMZ efficacy. The proposed studies will provide new biomarkers of response to temozolomide-induced DNA damage and cell death and provide insight into mechanisms that can be exploited to enhance response and to identify novel targets for adjuvant therapies.
|Srivas, Rohith; Shen, John Paul; Yang, Chih Cheng et al. (2016) A Network of Conserved Synthetic Lethal Interactions for Exploration of Precision Cancer Therapy. Mol Cell 63:514-25|
|Soll, Jennifer M; Sobol, Robert W; Mosammaparast, Nima (2016) Regulation of DNA Alkylation Damage Repair: Lessons and Therapeutic Opportunities. Trends Biochem Sci :|
|Fouquerel, Elise; Lormand, Justin; Bose, Arindam et al. (2016) Oxidative guanine base damage regulates human telomerase activity. Nat Struct Mol Biol 23:1092-1100|
|Moretti, Andrea; Li, Jianfeng; Donini, Stefano et al. (2016) Crystal structure of human aldehyde dehydrogenase 1A3 complexed with NAD(+) and retinoic acid. Sci Rep 6:35710|
|Sawant, Akshada; Kothandapani, Anbarasi; Zhitkovich, Anatoly et al. (2015) Role of mismatch repair proteins in the processing of cisplatin interstrand cross-links. DNA Repair (Amst) 35:126-36|
|Wendell, Stacy Gelhaus; Golin-Bisello, Franca; Wenzel, Sally et al. (2015) 15-Hydroxyprostaglandin dehydrogenase generation of electrophilic lipid signaling mediators from hydroxy Ï‰-3 fatty acids. J Biol Chem 290:5868-80|
|Brown, M F; Leibowitz, B J; Chen, D et al. (2015) Loss of caspase-3 sensitizes colon cancer cells to genotoxic stress via RIP1-dependent necrosis. Cell Death Dis 6:e1729|
|QuiÃ±ones, Jason L; Thapar, Upasna; Yu, Kefei et al. (2015) Enzyme mechanism-based, oxidative DNA-protein cross-links formed with DNA polymerase Î² in vivo. Proc Natl Acad Sci U S A 112:8602-7|
|Wang, Jingnan; Li, Jianfeng; Santana-Santos, Lucas et al. (2015) A novel strategy for targeted killing of tumor cells: Induction of multipolar acentrosomal mitotic spindles with a quinazolinone derivative mdivi-1. Mol Oncol 9:488-502|
|Chandran, Uma R; Luthra, Soumya; Santana-Santos, Lucas et al. (2015) Gene expression profiling distinguishes proneural glioma stem cells from mesenchymal glioma stem cells. Genom Data 5:333-336|
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