PIK3CA基因突变在子宫内膜癌发生发展中的作用及分子靶向治疗

The frequent activation of the PI3K signaling pathway in endometrial cancer justifies investigation of this signaling pathway as a major target for this disease. The success of molecularly targeted cancer therapies has invariably been challenged by the rapid emergence of drug resistance. Hence there is a crucial need for preclinical studies to uncover the molecular driver events that may affect tumor responses and confer drug resistance, and thus to inform the design of rational therapies and the right choice of agents evaluated in the clinic. Our previous works using genetic mouse models of women's cancers revealed that tumors addicted to the activated PI3K signaling pathway showed superior sensitivity to PI3K pathway inhibitors (Nat.Med.2011); in particular, Pten Lkb1 deficient endometrial cancers showed superior sensitivity to mTOR inhibition (Cancer Res.2014). To date, the role of frequent activating PIK3CA mutations in endometrial cancer remains elusive. In this project, we propose to establish a genetic mouse model of endometrial cancer harboring PIK3CAH1047R, a PIK3CA activating mutation frequently found in the corresponding human disease, as well as patient-derived xenograft models of endometrial cancer. Using these model systems, we will interrogate the impact of PIK3CAH1047R on the initiation and maintenance of endometrial cancer, evaluate the anti-tumor effects of PI3K inhibitors, identify and validate molecular driver events that are responsible for drug resistance. The long-term goal of this project is to define effective treatment strategies for endometrial cancer, leading to improved cure rates of women's cancer.

子宫内膜癌中PI3K传导通路频繁过度激活,探索子宫内膜癌中PI3K通路异常调控的作用机制并找到可用作药物靶标的关键异变基因意义重大。申请人前期研究发现，以PI3K为靶点的抑制剂对依赖PI3K通路的肿瘤有良好的抑制作用(Nat.Med.2011)；且PtenLkb1共缺失型子宫内膜癌对PI3K通路下游mTOR的抑制表现敏感(Cancer Res.2014)。但PIK3CA基因突变导致的PI3K通路激活在子宫内膜癌发生发展中的作用机制,目前尚不清楚。本项目拟构建可诱导表达人源PIK3CA突变基因的子宫内膜癌小鼠模型，通过诱导和去诱导该基因的表达研究PI3K-AKT-mTOR通路对子宫内膜癌发生、发展的影响,评估PI3K靶向抑制剂的治疗效果; 并结合人源子宫内膜癌移植瘤和获得性耐药癌细胞株模型，寻找PI3K靶向抑制剂耐药驱动因子。此研究将为防止复发和治愈PIK3CA突变型子宫内膜癌提供新思路。

子宫内膜癌中PI3K信号传导通路频繁过度激活，为明确其在子宫内膜癌发生发展中的作用，以及靶向PI3K通路在妇科肿瘤临床治疗中的意义，本课题组成功构建可诱导表达PIK3CAH1047R基因突变的子宫内膜癌遗传工程小鼠模型。以此模型为基础，通过诱导和去诱导PIK3CAH1047R基因表达，明确了癌基因PIK3CAH1047R是子宫内膜癌发生的重要驱动因子，并在肿瘤发展中也起到重要作用。进一步研究表明，泛PI3K抑制剂BKM120与PARP抑制剂Olaparib联用可协同抑制PI3K通路激活型子宫内膜癌的生长（Oncogene, 2018）。我们也将此联药策略拓展到PIK3CA突变型卵巢癌细胞系和动物模型的临床前研究中，取得了良好的治疗效果（Gynecol Oncol, 2016; Oncotarget, 2016）。我们的分子机制研究发现，PI3K抑制剂单药可下调BRCA1/2、RAD51等同源重组修复通路关键蛋白表达，造成细胞同源重组修复能力下降，DNA损伤加剧，与PARP抑制剂联用 “合成致死”杀伤肿瘤细胞。本项目的研究结果提示：通过与PI3K抑制剂联用，有望拓展PARP抑制剂在同源重组修复正常型妇科肿瘤中的临床治疗范围，具有良好的应用前景。与此同时，我们还逐步建立多种癌症临床前研究模型，包括病人源性肿瘤移植瘤膜型，活组织切片短期离体培养模型和条件性重编程细胞培养等。这些临床前癌症模型的系统联合使用，将为包括子宫内膜癌在内的妇科肿瘤的发生机制、分子靶向治疗及其耐药机制等研究提供重要研究工具，为实现基础研究向临床转化，提高妇科肿瘤治疗效果评估的准确性和可靠性，并为探寻基于PI3K抑制剂的联药方案治疗PI3K通路激活型妇科瘤患者的临床应用提供理论依据。