Project 4 - Characterizing and Overcoming Resistance to ERBB2 Directed Therapy in Metastatic Gastric and Esophageal Adenocarcinoma

项目摘要 ERBB 2在约20%的胃和食管腺癌（GEAs）中扩增， 转移性ERBB 2 + GEA用化疗和抗体的组合治疗 曲妥珠单抗然而，曲妥珠单抗在GEA中仅适度有效，并且所有其他靶向治疗均有效。 ERBB 2+乳腺癌的药物在GEA临床试验中失败。我们建议直接 解决我们假设介导ERBB 2治疗失败的两个主要因素， GEA：适应性抗性和遗传复杂性。为了进行这些研究，我们的团队 具有互补技能的研究人员将对最佳的 使用一系列患者来源的模型系统稳定抑制ERBB 2的方法。 此外，我们还将进行一项前瞻性的临床收集，涵盖多个大型学术研究， 我们评估治疗期间ERBB 2 + GEAs的遗传进化的医疗中心， 定义伴随抗性的遗传改变，然后在功能上验证机制 和最佳的联合治疗。我们还将探讨无细胞（cf）DNA的作用 基因组谱分析，以指导治疗，面对疾病的基因组演变， 疗法总体目标是验证候选耐药机制，并寻求 确定最佳的组合疗法，可以克服它们。我们因此建议 以下具体目的：目的1：确定对ERBB 2的适应性抗性的机制 在GEA患者样品中进行治疗，并开发最佳靶向组合以稳定抑制 GEA模型系统中的ERBB 2活性。目的2：通过以下方法评估耐药的遗传病因： 确定ERBB 2阴性亚克隆或ERBB 2阴性亚克隆导致耐药的频率 ERBB 2+肿瘤细胞中的次级基因组改变。目标3：从机制上验证 次级基因组改变促进曲妥珠单抗耐药和检测 联合治疗以克服耐药性。总之，我们将定义遗传和非遗传- 对ERBB 2治疗耐药的遗传机制。理想情况下，我们的研究将导致 开发在一线治疗中效果良好的活性/最佳候选疗法，以及 在对当前疗法产生获得性耐药性的肿瘤中。

Project Summary ERBB2 is amplified in ~20% of Gastric and esophageal adenocarcinomas (GEAs) and metastatic ERBB2+ GEAs are treated with a combination of chemotherapy and the antibody Trastuzumab. However, Trastuzumab is only modestly effective in GEA, and all other targeted agents in ERBB2+ breast cancer have failed in GEA clinical trials. We propose to directly address the two primary factors that we hypothesize to mediate failure of ERBB2 therapy in GEA: adaptive resistance and genetic complexity. To perform these studies, our team of investigators with complementary skill sets will both perform detailed assessment of optimal approaches to stably inhibit ERBB2 using an array of patient-derived model systems. Furthermore, we will perform a prospective clinical collection spanning multiple large academic medical centers in which we evaluate the genetic evolution of ERBB2+ GEAs during therapy, define genetic alterations that accompany resistance and then functionally validate mechanisms of resistance and optimal combination therapy. We will also explore the role of cell-free (cf)DNA genomic profiling to guide therapy in the face of genomic evolution of the disease during therapy. The overall goal will be to validate candidate resistance mechanisms and seek to define optimal combination therapies that can overcome them. We therefore propose the following Specific Aims: Aim 1: To define mechanisms of adaptive resistance to ERBB2 therapy in GEA patient samples and to develop optimal targeted combinations to stably inhibit ERBB2 activity in GEA model systems. Aim 2: To evaluate genetic etiologies of resistance by determining how frequently resistance results from ERBB2-negative subclones or from secondary genomic alterations in ERBB2+ tumor cells. Aim 3: To validate mechanistically the capacity of secondary genomic alterations to promote Trastuzumab resistance and to test combination therapies to overcome resistance. In summary, we will define genetic and non- genetic mechanisms of resistance to ERBB2 therapy. Ideally, our studies will lead to the development of active/optimal candidate therapies that work well in first-line therapy as well as in in tumors marked by acquired resistance to current therapy.