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

项目SUI\/11\/项目(请参阅说明)： 这项提案的目的是识别和验证生物标记物，这些生物标记物将首次 卵巢癌个体化治疗。因此，该提案将包括执行一项创新的 第二阶段临床试验，将促进验证预测临床疗效的新生物标志物 针对卵巢癌女性个体的靶向治疗。我们将针对两个生物过程，我们 另一些已被证实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’)，以及(Ii)缺陷 BRCA1/2介导的同源重组(‘BRCAness’)。这项建议将建立在成功的 针对卵巢癌Pisk信号通路的I期试验，我们在之前的 孢子资助期。它还将建立在我们的新数据基础上，表明体细胞突变和基因缺失 BRCA1和BRCA2功能在卵巢癌和卵巢癌中比之前认为的更常见 应预测对表现为合成的聚腺苷二磷酸核糖聚合酶(PARP)抑制剂(PARPI)的敏感性 BRCA1/2功能障碍的致命性。这项建议将汇集：1.西南肿瘤学小组 (SWOG)促进第二阶段试验的执行，2.阿斯特拉捷利康提供获得新疗法的途径 Olaparib(PARPI)和AZD8055(Pisk途径抑制剂)，以及3.Myriad Genetics，Inc.。具体目标是： 目标1：确定PISKness是否预测细胞系对Pisk途径抑制剂的反应性 和卵巢癌异种移植。B.确定‘PISKness’是否可以预测卵巢癌的预后 接受手术和以铂/紫杉醇为主的化疗的患者。 目的2；A.确定‘BRCAness’是否预测细胞系对PARP抑制剂的反应性和 卵巢癌异种移植瘤。B.确定“BRCAness”是否可以预测卵巢癌的预后 接受手术和以铂/紫杉醇为主的化疗的患者。 目的S；确定PISK/AKT/mTOR靶向是否能预测PISK/AKT/mTOR靶向反应 PATH和PARP分别在卵巢癌II期临床试验中使用。

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.