The Regulation of Cisplatin resistance in ovarian cancer

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DESCRIPTION (provided by applicant): The Regulation of Cisplatin Resistance in Ovarian Cancer Ovarian cancer (OCa) is the fifth most common cancer among women. It causes more deaths than any other type of female reproductive cancer. Platinum-based drugs including cisplatin are the standard treatment for OCa. The therapeutic benefit of cisplatin depends on its ability to induce DNA damage such as DNA crosslinks and trigger cell death. In addition to cell death, cisplatin-induced DNA damage can also be repaired, leading to cell survival. The latter outcome results in reduced cisplatin efficacy and the development of cisplatin resistant ovarian cancer (CROC). Indeed, the majority of ovarian cancer patients eventually develops resistance to this drug and dies with progressive chemoresistant disease. Cisplatin- refractory is a major problem that undermines efforts to effectively treat OCa. Therefore, it is urgent to elucidate the mechanisms responsible for cisplatin resistance and then develop new approaches to treat CROC effectively. Homologous recombination (HR) is involved in cisplatin resistance of OCa by repairing cisplatin-induced DNA damage. However, molecular mechanism governing HR repair in CROC remains elusive. We recently reported that And-1 (acidic nucleoplasmic DNA-binding protein) plays multiple roles in the regulation of genomic stability. Our preliminary studies indicate that And-1 is also involved in HR repair and a combination of And-1 inhibition and cisplatin results in CROC cell death in a synergistic manner. We hypothesize that And-1 contributes to cisplatin resistance by promoting HR repair in CROC. To test this hypothesis, we propose to determine 1) how And-1 contributes to cisplatin resistance by regulating HR repair in CROC cells; 2) to analyze the extent to which And-1 levels contribute to cisplatin resistance of CROC in vivo; 3) to examine whether a combination of And-1 inhibition by a newly identified compound and cisplatin is a novel avenue for treatment of CROC. We anticipate that completion of proposed studies will not only fill in a critical knowledge gap of cisplatin resistance in CROC but also provide an innovative potential therapeutic strategy as well as a potential drug for treatment of CROC.