Selective targeting of tumor cell redox metabolism and DNA damage responses to enhance cancer therapy

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Project Summary Lung cancer is the most commonly diagnosed and deadliest cancer in the world, accounting for over nearly one-fifth of all cancer deaths in 2018, and the 5-year survival rate for non-small cell lung cancer (NSCLC) is only 18.1%. Given these poor outcomes, new treatment approaches that selectively target cancer cells are urgently needed. Despite the recent interest in the field of cancer redox metabolism, the link between cancer redox metabolism and DNA damage repair/signaling as a means by which to enhance tumor cell responses to radio-chemotherapies remains largely unexplored. My Ph.D. thesis work seeks to exploit inherent differences in cancer cell NAD+ metabolism to sensitize cancer cells to radio-chemo-therapies. We hypothesize that selective depletion of NAD(P)(H) in NSCLC cells (versus normal cells) with nicotinamide phosphoribosyltransferase (NAMPT) inhibitors will confer potent radio-chemo-sensitization by inducing hydroperoxide-mediated metabolic oxidative stress and/or persistence of cytotoxic PARP- DNA complexes. My preliminary data supports this hypothesis and, in the remaining F99 phase, a causal link between the radio-chemo-sensitizing effects of NAMPT inhibition on metabolic oxidative stress and/or persistent PARP1-DNA complex formation will be established. I will continue by investigating DNA damage signaling/repair and cancer cell redox metabolism as a post-doctoral researcher studying the relationship between ataxia telangiectasia mutated (ATM) and dysregulated cancer cell redox metabolism with the goal of enhancing cancer cell responses to radio-chemotherapies. Overall, I believe that this F99/K00 award will provide the means for me to utilize my skills as a redox biologist in order to establish a research career focused on the role of cancer cell redox metabolism and DNA damage repair/signaling in tumor cell responses to radio-chemotherapies.