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

项目摘要 ERBB2在约20%的胃腺癌和食管腺癌(GEA)中扩增 化疗联合抗体治疗转移性ERBB2+GEA 曲妥珠单抗。然而，曲妥珠单抗在GEA和所有其他靶向治疗中只有一定的效果 ERBB2+乳腺癌的药物在GEA临床试验中失败了。我们建议直接 解决我们假设的导致ERBB2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 拥有互补技能的调查人员都将执行最优 使用患者衍生模型系统阵列稳定抑制ERBB2的方法。 此外，我们将进行一项跨越多个大型学术机构的前瞻性临床收集 我们在医学中心评估ERBB2+GEA在治疗过程中的遗传进化， 确定伴随抗性的基因改变，然后从功能上验证机制 耐药和最佳联合治疗。我们还将探索无细胞(Cf)DNA的作用。 面对疾病的基因组进化，基因组图谱以指导治疗 心理治疗。总体目标将是验证候选抵抗机制并寻求 确定可以克服它们的最佳组合疗法。因此，我们建议 以下具体目标：目标1：确定对ERBB2的适应性抗性机制 在GEA患者样本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ERBB2活性。目的2：通过以下方法评估耐药性的遗传病因 确定ERBB2阴性亚克隆产生抗性的频率 ERBB2+肿瘤细胞的继发性基因组改变。目标3：机械地验证 次级基因组改变促进曲妥珠单抗耐药性和测试的能力 克服耐药性的联合疗法。总之，我们将定义遗传性和非遗传性 ERBB2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主动/最佳候选疗法以及 在对当前治疗具有获得性抗药性的肿瘤中。

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.