Ovarian cancer is a leading cause of death from gynecologic malignancies with an overall survival rate of less than 40%. One of the most popular approaches for treating ovarian cancer is targeted therapy by a drug called PARP inhibitor. The drug exploits specific weaknesses of cancer cells to kill them and has a limited effect on normal cells. PARP is involved in DNA damage repair in the patient. Since ovarian cancer patients are often defective in their ability to repair damaged DNA, PARP inhibitor treatment leads to the accumulation of DNA damage. However, in many cases the cancer cells adapt to the drug and become resistant, and tumors ultimately progress. The resistance mechanisms for most patients are largely unclear. We attribute this to the additional active DNA repair systems in the tumor. Therefore, to increase the clinical benefits of PARP inhibitors, a systematic survey of actionable drug targets contributing to deficient DNA repair is critically needed to devise new strategies for ovarian cancer patients. We hypothesize that these PARP-based combination therapies would exhibit synergy and better killing of cancer cells. Our preliminary data analyses identified several such candidate target genes. Here we propose an integrative approach to systematically investigate regulatory factors involved in DNA repair, and a combination of computational and experimental approaches to unravel mechanisms for PARP inhibitor resistance and to evaluate novel combination therapies.
Because these new drug combinations overcome the limitations of DNA repair deficiency requirement by typical PARP-based monotherapies, we predict that the combination therapies devised here may apply to a large proportion of women with ovarian tumors, regardless of their DNA repair status. We expect that the results of this study will have major implications for understanding the mechanisms responsible for drug resistance, and for developing new combination therapeutic approaches for ovarian cancer patients with high risk of recurrence.