PTEN缺失型子宫内膜癌对PI3K催化亚基的依赖性及其分子靶向研究

The frequent loss of PTEN and activation of the PI3K pathway in endometrial cancer justifies investigation of PI3K as a major target for this disease. However, in clinical trials, PI3K targeted drugs, mostly pan‐PI3K inhibitors, have not yet yielded exciting results due to drug resistance and off-target effects. Recent preclinical studies have shown that different PI3K isoforms have divergent roles in cellular signaling and cancer, suggesting that inhibitors targeting individual isoforms may achieve greater therapeutic efficacy. We recently found that pan-PI3K inhibitor BKM120 treatment resulted in aggravated DNA damage response with concomitant BRCA downregulation and exacerbated homologous recombination repair deficiency, and that combined use of PI3K and PARP inhibitors synergistically blocked cancer cell growth in vitro and in vivo. Built upon these findings, we reason that PI3K catalytic isoform-specific inhibitor plus PARP inhibitor Olaparib is likely a more effective, less toxic combination therapy for PTEN-deficient endometrial cancer. To test this hypothesis, we recently generated a highly clinically relevant, genetic mouse model of Ptenp53 deficient endometrial cancer to interrogate the impact of p110α and p110β on the initiation and maintenance of Pten-deficient endometrial cancer. Using genetics and pharmacological intervention approaches, we will evaluate the therapeutic effects of PI3K inhibitors, including pan-inhibitors and isoform-specific inhibitors, as single agents and in combination with PARP inhibitor Olaparib, and investigate the underlying mechanism. We will also employ newly established patient-derived xenografts and ex vivo tumor tissue culture models to validate our findings. The long-term goal of this project is to define safe and effective treatment strategies for PTEN-deficient endometrial cancer with the hope to improved cure rates of women’s cancer.

PTEN缺失、PI3K信号通路过度激活在子宫内膜癌中频繁发生，靶向PI3K治疗子宫内膜癌前景广阔。然而，泛PI3K抑制剂治疗会产生耐药和副作用，成为靶向治疗的瓶颈。申请人前期研究发现：泛PI3K抑制剂可导致癌细胞中同源重组修复缺陷，若与PARP抑制剂联用则能显著抑制癌细胞生长。由此推测:找到驱动PTEN缺失型子宫内膜癌发生和发展的特异性PI3K催化亚基，并以之为靶点与PARP联合抑制将是有效且副作用小的靶向治疗方案。为此，本课题组成功构建Pten缺失型子宫内膜癌遗传工程小鼠模型，拟用遗传学与靶向药物干预手段，研究PI3K催化亚基p110α和p110β对Pten缺失型子宫内膜癌发生、发展的影响，评估各类PI3K抑制剂与PARP抑制剂单用或联用的治疗效果；结合癌细胞系、临床人原发子宫内膜癌移植瘤和活组织切片离体培养模型加以验证，并寻找监测疗效的分子标记物，为防治此类肿瘤耐药和复发提供新思路。

PTEN缺失导致PI3K通路过度激活在子宫内膜癌中频繁发生（高达67%），因此靶向PI3K通路对此类子宫内膜癌的治疗前景广阔。然而，越来越多的临床前和临床试验均表明：泛PI3K抑制剂单药治疗产生耐药和副作用，成为靶向治疗的瓶颈。本项目研究发现，泛PI3K抑制剂BKM120与PARP 抑制剂Olaparib 联用可协同抑制PTEN缺失型子宫内膜癌的生长（Oncogene, 2018）。PI3K 抑制剂通过下调BRCA1、RAD51 等同源重组修复关键因子的表达，削弱细胞同源重组修复DNA损伤的能力，与PARP 抑制剂联用 “合成致死”杀伤癌细胞。值得一提的是，我们进一步研究发现，PTEN缺失型肿瘤细胞对PI3K/PARP双抑制的联药方案更为敏感，提示PTEN可作为预测肿瘤细胞对PI3K/PARP联合抑制疗效的分子标志物。针对泛PI3K抑制剂副作用问题，本项目成功构建Ptenp53和PtenLkb1共缺失型子宫内膜癌遗传工程小鼠，分别通过遗传学与靶向药物干预手段，明确了PI3K催化亚基p110α，而非p110β，在PTEN缺失型子宫内膜癌发生、发展（维系）中的关键促癌作用。本研究为靶向p110α亚基治疗PTEN缺失型子宫内膜癌，降低泛PI3K抑制剂副作用，有效治疗及防止此类肿瘤耐药复发提供新思路。非常有意义的是，本项研究拓展了PI3K抑制剂（特别是于2019年获批临床肿瘤治疗的p110α亚基抑制剂BYL719）以及PARP抑制剂在多种女性肿瘤中的应用（Cancer Letters, 2019；Ebiomedicine, 2019）。此外，我们还建立了临床子宫内膜肿瘤样本的类器官模型，为基于PI3K 抑制剂的联药方案治疗包括PTEN缺失型子宫内膜癌在内的女性肿瘤的临床应用研究提供理论依据，为快速、有效和精准性的临床用药指导，以及提高实现基础研究向临床应用转化提供重要的技术平台。