Targeting Wnt signaling to overcome PARP inhibitor resistance in ovarian cancer

 描述(申请人提供)：卵巢癌是美国最致命的妇科疾病，部分原因是缺乏对癌症如何对化疗产生抗药性的了解。已有的(顺铂)和新兴的抗癌药物(PARPI)的疗效在很大程度上依赖于固有的DNA损伤反应。最近的报道已经观察到顺铂耐药的癌细胞对PARP抑制剂具有交叉耐药性。卵巢癌的初步实验表明，异常的Wnt信号通过调节非同源末端连接(NHEJ)途径而参与顺铂和PARPI的耐药。这项研究的总体目标是阐明卵巢癌中Wnt依赖的PARPI/顺铂耐药的机制，并开发一种翻译方法来重新使肿瘤细胞敏感。在指导的K99阶段，我将致力于清楚地确定Wnt信号异常(例如，Wnt5a丢失)和NHEJ在传递或维持卵巢癌细胞的化疗耐药中所起的影响。然后，我将确定在抵抗疾病的背景下，抑制典型的Wnt和NHEJ通路的体内意义。我将致力于建立卵巢癌的临床前模型(患者来源 异种移植)，以确定Wnt信号或NHEJ的调节是否可以转化为临床环境，以帮助治疗化疗耐药的卵巢癌。令人兴奋的是，拟议中的 这项工作将有助于阐明耐药过程，并可能对未来卵巢癌的治疗策略产生直接影响。

 DESCRIPTION (provided by applicant): Ovarian cancer is the deadliest gynecological disease in the United States, which is due in part to the lack of understanding on how the cancer becomes resistant to chemotherapies. Established (cisplatin) and emerging anti-cancer therapeutics (PARPi) effectiveness rely heavily on intrinsic DNA damage response. Recent reports have observed that cisplatin-resistant cancer cells are cross-resistant to PARP inhibitors. Preliminary experiments in ovarian cancer indicate that aberrant Wnt signaling contributes to resistant to both cisplatin and PARPi by modulating the non-homologous end-joining (NHEJ) pathway. The overall goals of the proposed research is to elucidate the mechanism of Wnt-dependent PARPi/cisplatin resistant in ovarian cancer and to develop a translational approach to re-sensitize tumor cells. During the mentored K99 phase, I will work to clearly establish the impact aberrant Wnt signaling (e.g. loss off Wnt5a) and NHEJ has in conveying or maintaining chemoresistance in ovarian cancer cells. I will then determine the in vivo significance of inhibiting canonical Wnt and NHEJ pathways in the context of resistant disease. I will pursue the establishment of pre- clinical models of ovarian cancer (patient-derived xenograft) to determine if the modulation of Wnt signaling or NHEJ could be translated into the clinical setting to aid in the treatment of chemoresistant ovarian cancer. Excitingly, the proposed work will contribute to the elucidation of the resistant process and could have a direct impact on future therapeutic strategies for ovarian cancer.