The Regulation of Cisplatin resistance in ovarian cancer

卵巢癌顺铂耐药的调控

• 批准号: 8673956
• 负责人: Wenge Zhu
• 金额: $ 32.89万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8673956
• 关键词: Cancer Etiology; Cancer Patient; Cell Death; Cell Survival; Cessation of life; Chemicals; Chromatin; Cisplatin; DNA; DNA Damage; DNA-Binding Proteins; Data; Development; Disease; Drug resistance; Foundations; Genes; Genetic; Genome Stability; Knowledge; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Modification; Molecular; Mus; Oncogenes; Outcome; Pharmaceutical Preparations; Platinum; Play; Proteins; Publishing; Recruitment Activity; Refractory; Regulation; Reporting; Resistance; Resistance development; Role; Site; Solid; Testing; Therapeutic; Transgenic Mice; Tumor-Derived; Woman; Xenograft procedure; base; cancer cell; crosslink; high throughput screening; homologous recombination; in vivo; innovation; novel; novel strategies; overexpression; public health relevance; recombinational repair; repaired; research study; response; small hairpin RNA; standard care

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.

卵巢癌（Ovarian cancer，OCa）是一种常见的恶性肿瘤，在女性中占第五位。它比任何其他类型的女性生殖系统癌症造成更多的死亡。包括顺铂在内的铂类药物是OCa的标准治疗方法。顺铂的治疗益处取决于其诱导DNA损伤（如DNA交联）和触发细胞死亡的能力。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对这种药物产生耐药性，并死于进行性耐药疾病。顺铂难治性是一个主要问题，破坏了有效治疗OCa的努力。因此，迫切需要阐明顺铂耐药的机制，并开发新的有效治疗CROC的方法。同源重组（HR）通过修复顺铂诱导的DNA损伤参与OCa的顺铂耐药。然而，在CROC HR修复的分子机制仍然难以捉摸。我们最近报道了And-1（酸性核质DNA结合蛋白）在基因组稳定性的调节中起着多种作用。我们的初步研究表明，And-1也参与HR修复，并且And-1抑制和顺铂的组合以协同方式导致CROC细胞死亡。我们假设And-1通过促进CROC中HR修复而导致顺铂耐药。为了验证这一假设，我们提出确定1）And-1如何通过调节CROC细胞中的HR修复来促进顺铂抗性; 2）分析And-1水平在体内促进CROC的顺铂抗性的程度; 3）检查新鉴定的化合物和顺铂的And-1抑制的组合是否是治疗CROC的新途径。我们预计，完成拟议的研究将不仅填补了一个关键的知识差距顺铂耐药的CROC，但也提供了一个创新的潜在的治疗策略，以及一个潜在的药物治疗CROC。