基于PDO、PDX模型研究WEE1抑制剂在卵巢癌中的耐药机制及解决策略

卵巢癌是致死率极高的女性生殖系统恶性肿瘤；HGSOC由于存在广泛的TP53突变，被认为G1/S检查点存在缺陷，因此大家普遍认为G2/M检查点的关键激酶WEE1是卵巢癌中最有前景的治疗靶点。而阻碍其临床应用的主要原因有：原发性、继发性耐药的出现；缺乏可以准确反映卵巢癌分子多样性特点的研究模型，研究成果临床转化困难；药物敏感性Biomarker不明，难以确定适应性治疗的适宜患者群体。本研究拟通过建立卵巢癌的PDO、PDX模型，探明WEE1抑制剂在卵巢癌中的有效性，结合疗效与肿瘤组织的WES，RNA-seq数据分析，找出敏感性Biomarker；同时利用靶向质谱核苷酸代谢分析研究mTOR通路的激活如何影响核苷酸代谢从而协同WEE1i杀伤肿瘤的机制，阐明WEE1i联合mTORi组合的作用机制。本项目为卵巢癌的靶向治疗丰富了理论基础，进行了有效的临床前效应验证，为卵巢癌的治疗提供新的选择策略。

Ovarian cancer is the most lethal malignant cancer in the female reproductive system. HGSOC is characterized by universal TP53 mutations, which result in G1/S checkpoint deficiency. Therefore, it is hypothesized that the abrogation of the G2/M checkpoint with Wee1 inhibitor might preferentially sensitize TP53-defective ovarian cancer cells. The main reasons that hinder WEE1i clinical application are as follows: the emergence of primary and acquired drug resistance; Lack of proper preclinical model that can accurately reflect the molecular diversity of ovarian cancer, which limits preclinical research. And it is difficult to determine the appropriate population of patients to adapt to this targeted therapy. In this study, PDO and PDX models of ovarian cancer were established to explore the effectiveness of WEE1 inhibitors, combined with efficacy and tumor tissue WES, RNA-seq data analysis to find out sensitivity biomarkers. At the same time, the targeted mass spectrometry about nucleotide metabolism was used to study how the activation of the mTOR pathway affects nucleotide metabolism and cooperate with WEE1i to kill tumor cells, and to clarify the mechanism of WEE1i combined with the mTORi combination and sensitivity biomarkers. This project enriches the theoretical basis for the targeted therapy of ovarian cancer, verifies the preclinical effects, and provides a new strategy for the treatment of ovarian cancer.