P4 - Pers. Therapy for High-Grade Ovarian Cancer: Targeting PI3Kness & BRCAne

PROJECT SUI\/11\/IARY（参见说明）： 该提案的目的是识别和验证生物标志物，这将首次使 卵巢癌个体化治疗。因此，该提案将包括执行一项创新性的 II 期临床试验将有助于验证预测临床疗效的新型生物标志物 针对个别患有卵巢癌的女性进行靶向治疗。我们将针对两个生物过程 和其他人已经确定在上皮性卵巢癌的发病机制中发挥着关键作用：（i） 磷脂酰肌醇 3 激酶 (PISK/AKT/mTOR) 通路的激活（“PISKness”），以及 (ii) 缺陷 BRCA1/2 介导的同源重组 (HR)（“BRCAness”）。该提案将建立在成功的基础上 我们在之前执行的针对卵巢癌 PISK 信号通路的 I 期试验 SPORE资助期。它还将以我们的新数据为基础，表明体细胞突变和丧失 BRCA1 和 BRCA2 功能在卵巢癌中比之前认为的更为常见，并且 应预测对表现出合成的聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）的敏感性 BRCA1/2 功能障碍导致死亡。该提案将汇集： 1. 西南肿瘤学小组 (SWOG) 以促进 II 期试验的执行，2. 阿斯利康 (Astra Zeneca) 提供新疗法 olaparib (PARPi) 和 AZD8055（PISK 通路抑制剂），以及 3. Myriad Genetics, Inc. 具体目标是： 目标 1：A. 确定“PISKness”是否可以预测细胞系对 PISK 通路抑制剂的反应 和卵巢癌异种移植物。 B. 确定“PISKness”是否可以预测卵巢癌的结果 接受手术和铂类/紫杉醇化疗的患者。 目标2； A. 确定“BRCAness”是否可以预测细胞系和 PARP 抑制剂的反应性 卵巢癌异种移植。 B. 确定“BRCAness”是否可以预测卵巢癌的结果 接受手术和铂类/紫杉醇化疗的患者。 瞄准S；确定“PISKness”和“BRCAness”是否可以预测针对 PISK/AKT/mTOR 的反应 途径和 PARP 分别在 II 期卵巢癌临床试验中。

PROJECT SUI\/11\/IARY (See instructions): The aim of this proposal is to identify and validate biomarkers that will, for the first time, enable individualization of therapy in ovarian cancer. This proposal will thus include the execution of an innovative phase II clinical trial that will facilitate the validation of novel biomarkers that predict the clinical efficacy of targeted therapies in individual women with ovarian cancer. We will target two biologic processes that we and others have established as playing critical roles in the pathogenesis of epithelial ovarian cancer: (i) activation of the phosphatidylinositide-3-kinase (PISK/AKT/mTOR) pathway ('PISKness'), and (ii) deficient BRCA1/2-mediated homologous recombination (HR) ('BRCAness'). This proposal will build on the successful phase I trial targeting the PISK signaling pathway in ovarian cancer thay we executed in the previous SPORE funding period. It will also build on our new data indicating that somatic mutations and loss of BRCA1 and BRCA2 function are significantly more common than previously thought in ovarian cancer and should predict sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) that exhibit synthetic lethality with BRCA1/2 dysfunction. This proposal will bring together: 1. the SouthWest Oncology Group (SWOG) to facilitate execution of the phase II trial, 2. Astra Zeneca to provide access to the novel therapies olaparib (PARPi) and AZD8055 (PISK pathway inhibitor), and 3. Myriad Genetics, Inc. The specific aims are: Aim 1: A. To determine whether 'PISKness' predicts responsiveness to PISK pathway inhibitors in cell lines and ovarian cancer xenografts. B. To determine whether 'PISKness' predicts outcome in ovarian cancer patients treated with surgery and platinum/paclitaxel-based chemotherapy. Aim 2; A. To determine whether 'BRCAness' predicts responsiveness to PARP inhibitors in cell lines and ovarian cancer xenografts. B. To determine whether "BRCAness" predicts outcome in ovarian cancer patients treated with surgery and platinum/paclitaxel-based chemotherapy. Aim S; To determine whether 'PISKness' and 'BRCAness' predict response to targeting the PISK/AKT/mTOR pathway and PARP, respectively, in a phase II ovarian cancer clinical trial.