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

项目SUI\/11\/IARY（参见说明）： 该提案的目的是确定和验证生物标志物，这将首次使 卵巢癌的个体化治疗因此，该提案将包括执行一项创新的 II期临床试验，这将有助于验证新的生物标志物，预测的临床疗效 卵巢癌的治疗方法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起关键作用：（i） 磷脂酰肌醇-3-激酶（PISK/AKT/mTOR）途径的激活（“PISKness”），和（ii）缺乏 BRCA 1/2介导的同源重组（HR）（“BRCAness”）。该提案将建立在成功的 一项针对卵巢癌中PISK信号通路的I期试验，我们在之前的研究中进行了这项试验。 融资期。它还将建立在我们的新数据基础上，这些数据表明，体细胞突变和基因丢失可能会导致基因突变。 BRCA 1和BRCA 2功能在卵巢癌中比以前认为的更常见， 应该预测对聚（ADP-核糖）聚合酶（PARP）抑制剂（PARPi）的敏感性， BRCA 1/2功能障碍的致命性。该提案将汇集：1。西南肿瘤组 （SWOG），以促进第二阶段试验的执行，2。Astra Zeneca提供新疗法 奥拉帕尼（PARPi）和AZD 8055（PISK途径抑制剂），和3. Myriad Genetics，Inc.具体目标是： 目标1：A.确定“PISKness”是否可预测细胞系对PISK通路抑制剂的反应性 和卵巢癌异种移植物。B。确定“PISKness”是否可预测卵巢癌的结局 接受手术和铂类/紫杉醇化疗的患者。 Aim 2; A.为了确定“BRCAness”是否预测细胞系中对PARP抑制剂的反应性， 卵巢癌异种移植物。B。确定“BRCAness”是否可预测卵巢癌的预后 接受手术和铂类/紫杉醇化疗的患者。 目的S：确定“PISK性”和“BRCAness”是否预测对靶向PISK/AKT/mTOR的应答 pathway和PARP，分别用于卵巢癌II期临床试验。

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.