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Inhibiting a DNA damage control mechanism as a strategy to selectively kill lung cancer cells

Institution: University of California, Los Angeles
Investigator(s): MICHAEL KRONENBERG,
Award Cycle: 2019 (Cycle 30) Grant #: T30DT0906 Award: $142,203
Subject Area: Cancer
Award Type: Dissertation Awards

Initial Award Abstract
Modern sequencing technology has revolutionized cancer drug development through enabling researchers to pinpoint the exact genes, or drivers, that enable different kinds of tumors to grow. This technology has drastically increased the survival rates for cervical, breast, and testicular cancer patients among others. Despite these advancements, progress in our ability to treat lung cancer has remained stagnant, evidenced by a still dismal survival rate. Lung cancer is physiologically unique in that its genome is highly unstable, or in other words, it mutates its genes very quickly. Thus, it is difficult to leverage sequencing technology to pinpoint genes to therapeutically target, as mutated genes are rarely the same between patients. Moreover, while some mutated genes have been identified as recurring in small patient populations and have available therapies, patients often relapse after an initial period of remission. This is likely due to the ability of lung cancer to mutate rapidly and thus develop secondary growth and survival pathways. Therefore, it would be prudent to develop alternate strategies to target lung cancer outside of driver mutation-based therapies. Paradoxically, the rapid mutation rate that makes lung cancer hard to treat with modern drug development strategies makes it vulnerable to ‘old school’ drugs. For example, chemotherapeutic agents such as cisplatin have been the front-line therapy for the last 30 years. Cisplatin is genotoxic; it damages DNA in cells, and thereby kills them. Because the genome in lung cancer is unstable and thus has high levels of DNA-damage to begin with, its ability to buffer additional damage from cisplatin is impaired relative to healthy cells. However, cisplatin at therapeutic dosages still generates damage in healthy tissue, inducing side-effects such as toxicity in the kidneys. Selectively inducing DNA-damage in tumor cells by inhibiting cancer genes that prevent damage accumulation is an intriguing alternate strategy for treatment. Interestingly, a protein complex named INO80C is over-active in lung cancer, and acts to prevent DNA damage only in cancer-like conditions. We propose that inhibition of INO80C activity will selectively amplify cisplatin's toxicity in lung cancer cells, enabling lower dosages that promote increased efficacy in killing cancer cells and decreased off-target toxicity in patients.