The Regulation of Cisplatin resistance in ovarian cancer

描述(申请人提供)：卵巢癌顺铂耐药的调节卵巢癌(OCA)是女性第五大常见癌症。它导致的死亡比任何其他类型的女性生殖癌都要多。包括顺铂在内的铂类药物是OCA的标准治疗方法。顺铂的治疗效益取决于其诱导DNA损伤的能力，如DNA交联和触发细胞死亡。除了细胞死亡外，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对这种药物产生抗药性，并死于进行性耐药疾病。顺铂耐药是破坏有效治疗OCA的努力的主要问题。因此，迫切需要阐明顺铂耐药的机制，进而开发有效治疗鳄鱼的新方法。同源重组(HR)通过修复顺铂诱导的DNA损伤参与OCA对顺铂的耐药。然而，调控鳄鱼HR修复的分子机制仍然不清楚。我们最近报道了酸性核质DNA结合蛋白(AND-1)在基因组稳定性调节中的多种作用。我们的初步研究表明，And-1也参与HR修复，And-1抑制和顺铂以协同方式导致鳄鱼细胞死亡。我们推测And-1通过促进鳄鱼的HR修复而参与顺铂耐药。为了验证这一假设，我们建议确定1)And-1如何通过调节鳄鱼细胞的HR修复来促进顺铂耐药；2)分析And-1水平在体内对鳄鱼顺铂耐药的贡献程度；3)研究一种新发现的化合物和顺铂联合抑制And-1是否是治疗鳄鱼顺铂的新途径。我们预计，拟议研究的完成不仅将填补鳄鱼对顺铂耐药性的关键知识空白，还将提供一种创新的潜在治疗策略，以及一种治疗鳄鱼的潜在药物。

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.