P4: A Framework for Identification of Novel Targeted Therapy Combinations in Endometrial Cancer

项目4 -概要/摘要 子宫内膜癌（EC）是最常见的妇科恶性肿瘤，也是第四大常见癌症 在美国的女性中。虽然治愈是可能的早期疾病，结果的患者 转移性或复发性疾病在过去二十年中没有显著改善。基于广泛 通过我们的团队和癌症基因组图谱的表征，EC在 靶向途径包括磷脂酰肌醇3激酶（PI 3 K，92%）、ARID 1A（33%）和同源 重组（HR 22%核心和77%延伸成员）途径。然而，迄今为止， 对欧盟没有重大影响。因此，如何利用EC中的治疗机会， 代表本应用程序总体目标的知识方面的重大差距。 我们的总体目标是：设计和实施合理的联合治疗临床试验， 高质量的临床和临床前数据和模型，以改善EC患者的结局。 目的1在PARP和PI 3 K通路的联合试验中识别和细化获益的生物标志物 EC的靶向治疗：基于EC中存在的潜在突变畸变，我们正在积极招募 在第一个信息丰富的，活检嵌入式肿瘤启动的试验中，针对PI 3 K通路中的两个节点， (mTOR（2个剂量方案）和AKT）与有效的“捕获”PARP抑制剂奥拉帕尼组合。我们 将检验这一假设，即PI 3 K通路中关键节点的联合靶向和PARP抑制将 在EC患者中证明获益。对治疗前和治疗后活检的DNA进行广泛表征， RNA和蛋白质水平将有助于识别有益的生物标志物，包括我们目前的一套生物标志物。 对PARP和PI 3 K通路抑制剂的反应性生物标志物。这是一个独特的方法和机会， 我们的证据支持PI 3 K和HR通路异常在EC中非常常见，可能导致 对PI 3 K和PARP通路联合抑制敏感的患者。 目的2建立一个临床前框架，以确定EC的合理联合靶向治疗， 在未来的EC临床试验中进行评估：对靶向治疗的适应性耐药性的出现有助于 单一疗法缺乏疗效。我们已经使用了我们的组合自适应阻力（CART）平台 确定有限数量的潜在额外合理组合进行验证，旨在适应 通过靶向DNA损伤反应诱导的抗性。该目标将侧重于体外和体内临床前 数据和生物标志物，以便在未来的试验中优先考虑组合。为了快速地将这些合理的药物 阿斯利康已签署合同，为EC临床试验提供资金， 完整的治疗管道。

Project 4 – SUMMARY/ABSTRACT Endometrial cancer (EC) is the most frequent gynecologic malignancy and the fourth most common cancer among women in the United States. Although cure is possible for early disease, outcomes for patients with metastatic or recurrent disease have not improved significantly over the last two decades. Based on extensive characterization by our team and The Cancer Genome Atlas, EC has a high frequency of aberrations in targetable pathways including the phosphatidylinositol 3 kinase (PI3K, 92%), ARID1A (33%), and homologous recombination (HR 22% core and 77% extended members) pathways. However, to date, targeted monotherapies have not had a major impact in EC. Thus, how to leverage the therapeutic opportunities in EC represents a major gap in knowledge that represents the overarching goal of this application. Our overall goal is: to design and implement rational combination therapy clinical trials based on high quality clinical and preclinical data and models to improve outcomes for EC patients. Aim 1 To identify and refine biomarkers of benefit in a combination trial of PARP and PI3K pathway targeted therapy in EC: Based on the underlying mutational aberrations present in EC, we are actively enrolling on the first information-rich, biopsy-embedded investigator-initiated trial targeting two nodes in the PI3K pathway (mTOR (2 dose schedules) and AKT) in combination with an effective “trapping” PARP inhibitor, olaparib. We will test the hypothesis that combined targeting of key nodes in the PI3K pathway and PARP inhibition will demonstrate benefit in EC patients. Extensive characterization of pre- and post-treatment biopsies at the DNA, RNA and protein levels will facilitate the identification of biomarkers of benefit including our current suite of biomarkers of responsiveness to PARP and PI3K pathway inhibitors. This is a unique approach and opportunity, supported by our evidence that PI3K and HR pathways aberrations are extremely common in EC, likely rendering patients sensitive to combined PI3K and PARP pathway inhibition. Aim 2 To establish a preclinical framework to identify rational combination targeted therapies for EC to be evaluated in future EC clinical trials: Emergence of adaptive resistance to targeted therapies contributes to the lack of efficacy of monotherapy. We have used our Combinatorial Adaptive Resistance (CART) platform to identify a limited number of potential additional rational combinations for validation, aimed at adaptive resistance induced by targeting the DNA damage response. This Aim will focus on in vitro and in vivo preclinical data and biomarkers to prioritize combinations in future trials. To rapidly translate these rational drug combinations to clinical trials in this SPORE, AstraZeneca has signed a contract to provide funding for EC clinical trials with their complete therapeutic pipeline.