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

项目4--摘要/摘要 子宫内膜癌(EC)是妇科最常见的恶性肿瘤，居第四位。 在美国的女性中。虽然早期疾病是有可能治愈的，但患有 在过去的二十年里，转移性或复发性疾病并没有明显改善。基于广泛的 通过我们的团队和癌症基因组图谱的鉴定，EC在 靶向通路包括磷脂酰肌醇3激酶(PI3K，92%)、ARID1A(33%)和同源物 重组途径(HR 22%的核心成员和77%的扩展成员)。然而，到目前为止，靶向单一疗法 没有在欧共体产生重大影响。因此，如何利用EC的治疗机会代表了 代表此应用程序总体目标的知识方面的主要差距。 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患者的预后。 目的1在PARP和PI3K途径联合试验中识别和提炼有益的生物标志物 EC中的靶向治疗：基于EC中潜在的突变异常，我们正在积极招募 在第一个以PI3K通路中的两个节点为靶点的信息丰富的、植入活检的研究人员发起的试验中 (mTOR(2个剂量计划)和AKT)与有效的PARP抑制剂olaparib联合使用。我们 将检验这样一种假设，即联合靶向PI3K通路的关键节点和抑制PARP将 展示对EC患者的益处。对DNA治疗前和治疗后的活检进行了广泛的表征， 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 对PARP和PI3K途径抑制剂反应的生物标志物。这是一种独特的方法和机会， 我们的证据支持PI3K和HR通路异常在EC中非常常见，很可能呈现 对联合抑制PI3K和PARP通路敏感的患者。 目的2建立一个临床前框架，以确定合理的联合靶向治疗食管癌 在未来的EC临床试验中被评估：对靶向治疗的适应性耐药的出现有助于 单一疗法的效果不佳。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附加合理组合以进行验证，目标是适应性 通过靶向DNA损伤反应而诱导的抗性。这一目标将集中在体外和体内的临床前 数据和生物标记物，在未来的试验中确定组合的优先顺序。为了快速翻译这些合理的药物 在这个孢子的临床试验中，阿斯利康已经签署了为EC临床提供资金的合同 具有完整治疗流水线的试验。

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.