Targeting Wnt signaling to overcome PARP inhibitor resistance in ovarian cancer

 描述（由申请人提供）：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耐药性的了解。已建立的（顺铂）和新兴的抗癌疗法（PARPi）的有效性在很大程度上依赖于内在的DNA损伤反应。最近的报道已经观察到顺铂耐药癌细胞对PARP抑制剂具有交叉耐药性。在卵巢癌中的初步实验表明，异常Wnt信号传导通过调节非同源末端连接（NHEJ）途径而有助于对顺铂和PARPi两者的抗性。这项研究的总体目标是阐明卵巢癌中Wnt依赖性PARPi/顺铂耐药的机制，并开发一种使肿瘤细胞重新敏感的转化方法。在指导K99阶段，我将致力于清楚地确定异常Wnt信号传导（例如Wnt 5a的丢失）和NHEJ在卵巢癌细胞中传递或维持化疗耐药性的影响。然后我将确定在耐药疾病的背景下抑制经典Wnt和NHEJ途径的体内意义。我将继续建立卵巢癌的临床前模型（患者来源的 异种移植物）中进行，以确定Wnt信号传导或NHEJ的调节是否可以转化为临床环境以帮助治疗化学抗性卵巢癌。令人兴奋的是， 这项工作将有助于阐明耐药过程，并可能对卵巢癌未来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.