Anti-miR-182治疗高级别浆液性卵巢癌耐药模型建立及机制研究

Ovarian cancer is the most fatally malignant gynecologic malignancy. Tumor heterogeneity and acquired resistance of platinum-based chemotherapy are the major causes of failure and death of high-grade serous ovarian cancer (HGSOC). Therefore, finding more specific and sensitive therapeutic targets, expounding resistance mechanism are the hot and difficult issues. Anti-miR-182, as the new anti-tumor target drug, was previously confirmed by our research group the significant inhibition role of growth, invasion and metastasis in HGSOC cell lines. At the same time, HGSOC patient-derived xenograft (PDX) model was successfully constructed to simulate the growth, metastasis and treatment of human HGSOC. Based on the Anti-miR-182 treatment of HGSOC PDX model, our research group will first prove that Anti-miR-182 can be used for patient-derived HGSOC treatment. Secondly, we will find and clarify the mechanism of Anti-miR-182 resistance. Third, we will validate the effect of inhibitor of specific drug resistance gene combined with Anti-miR-182 treatment. This study will promote the clinical transformation of Anti-miR-182 in the treatment of HGSOC with a goal to achieve individual and precision treatment of HGSOC.

卵巢癌是病死率最高的妇科恶性肿瘤，肿瘤异质性和常规铂类化疗的获得性耐药是高级别浆液性卵巢癌（HGSOC）治疗失败和死亡的重要原因，因此寻找更特异、敏感的治疗靶点，解析HGSOC耐药机制，是当前研究的热点和难点。Anti-miR-182作为新型抗肿瘤靶向药物，课题组前期已证实其可显著抑制HGSOC细胞系生长、侵袭和转移。同时构建HGSOC患者源性异体移植（PDX）模型，模拟人HGSOC生长、转移及治疗情况。课题组拟以Anti-miR-182治疗HGSOC PDX原位移植模型为主线，首先明确Anti-miR-182可用于患者源性HGSOC治疗；其次明确介导Anti-miR-182治疗HGSOC的耐药基因并明确其耐药机制；再次验证耐药基因抑制剂联合Anti-miR-182治疗HGSOC的疗效。本课题将推动Anti-miR-182治疗HGSOC的临床转化，以期实现HGSOC的精准和个体化治疗。

卵巢癌是病死率最高的妇科恶性肿瘤，肿瘤异质性和化疗耐药是高级别浆液性卵巢癌（HGSOC）治疗失败和死亡的重要原因，靶向治疗是近年来卵巢癌治疗研究热点，但其同样存在治疗耐药问题。本研究着眼于卵巢癌最新靶向治疗制剂PARPi，以及新型抗肿瘤靶向药物miRNA制剂，在卵巢癌PDX动物模型中进行了一系列研究，探索了治疗耐药相关机制及可能改善耐药的相关策略。本研究首先成功构建了稳定可传代的HGSOC PDX模型，模拟人HGSOC生长、转移及治疗情况。其次明确了Anti-miR-182可用于患者源性HGSOC治疗，并发现其有效率为50%。再次筛选出了卵巢癌铂敏感相关的miR-509-3，并证实其通过调控DNA损伤修复相关通路，在HGSOC中起到抑癌作用。最后在HGSOC的PDX模型中进行PARPi和/或miR-509-3治疗，结果显示二者具有协同作用。本课题将推动Anti-miR-182及MiR-509-3治疗HGSOC的临床转化，为提高HGSOC患者的PARPi反应性、逆转耐药提供新的潜在治疗策略。