The Regulation of Cisplatin resistance in ovarian cancer

卵巢癌（OCa）是女性第五大常见癌症。它造成的死亡人数超过任何其他类型的女性生殖癌症。包括顺铂在内的铂类药物是OCa的标准治疗方法。顺铂的治疗效果取决于其诱导DNA损伤（如DNA交联）和引发细胞死亡的能力。除了细胞死亡，顺铂诱导的DNA损伤也可以修复，导致细胞存活。后一种结果导致顺铂疗效降低和顺铂耐药卵巢癌（CROC）的发展。事实上，大多数卵巢癌患者最终会对这种药物产生耐药性，并死于渐进性化疗耐药疾病。顺铂难治性是影响有效治疗OCa的主要问题。因此，迫切需要阐明顺铂耐药机制，进而开发有效治疗CROC的新方法。同源重组（Homologous recombination， HR）通过修复顺铂诱导的DNA损伤参与了OCa的顺铂耐药。然而，调控CROC中HR修复的分子机制尚不明确。我们最近报道了And-1（酸性核质dna结合蛋白）在基因组稳定性调控中发挥多种作用。我们的初步研究表明and -1也参与HR修复，并且and -1抑制和顺铂的联合作用以协同方式导致CROC细胞死亡。我们假设And-1通过促进CROC中HR修复来促进顺铂耐药。为了验证这一假设，我们建议确定1)And-1如何通过调节CROC细胞中的HR修复来促进顺铂耐药；2)分析And-1水平对体内CROC顺铂耐药的影响程度；3)研究新发现的化合物与顺铂联合抑制and -1是否为治疗CROC的新途径。我们预计，上述研究的完成不仅将填补CROC顺铂耐药的关键知识空白，而且还将提供一种创新的潜在治疗策略以及治疗CROC的潜在药物。

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.