Bay Area Team Against Resistance

项目摘要 拟议的湾区抵抗U 54项目团队（BATAR-UP）是一项跨学科的努力， 研究人员运用他们的知识和专业知识，剖析不完整的分子和细胞基础， 对当前治疗的反应和耐药性，并确定新的治疗策略，以更好地中和或 消灭残病，防止抗药性。这种转化方法将成为NCI药物的一部分， 抵抗和敏感中心网络，以制定创新战略，了解和打击 肿瘤耐药机制和开发肿瘤对抗癌疗法的敏感性。 为了实现这一目标，BATAR-UP将支持两个项目和一个由多学科驱动的核心项目。 加州大学旧金山分校和斯坦福大学的一个研究小组。项目1将定义和询问分子和 临床应用靶向抑制剂治疗肺癌中残留疾病的细胞基础。我们将优先考虑 对于EGFR突变型和ALK基因重排阳性肺癌的初步研究， 作为关键分子疾病亚型和我们先前发表的工作和专业知识。我们将利用基因和 临床样品（液体和肿瘤活检）的转录组学分析，以提供 反应、残留疾病和获得性耐药性的演变。我们将生成类器官和PDX模型 并应用尖端的功能筛选（遗传学，药理学和靶向蛋白质组学测定）来识别 关键的弱点，可以治疗利用，包括与CTEP代理。这种系统性 这种方法将使我们能够揭示驱动EGFR的不完全反应和残留疾病的基础 和ALK抑制剂耐药性，并确定治疗策略，以阻止残留疾病的发展 最终获得抵抗力项目2将定义和询问的分子和细胞的基础， 目前的免疫疗法，包括PD-1和PD-2， L1抗体。利用共享平台与项目1的协同作用，我们将进行系统分析， 液体和肿瘤活检标本（和离体模型）， 在治疗期间和获得性耐药性时。我们将重点研究EGFR和ALK野生型患者， 包括免疫疗法显示有效的鳞状细胞肺癌和腺癌患者 但通常是非治愈性的。我们将利用（1）一种新的肺癌类器官模型，其中肿瘤活检 作为肿瘤上皮细胞和它们的内源性肿瘤浸润淋巴细胞（TIL）整体培养， 内聚单元，和（2）基于深液滴的单细胞RNA-seq分析。我们的系统方法将有助于 明确导致免疫治疗耐药性的不完全应答和残留疾病的基础 并确定潜在的新的治疗策略，以帮助将这些不完全的反应转化为治愈性反应， 结果。我们的行政核心将为BATAR-UP提供领导、协调和监督， 协同两个项目和整个DRSC网络中进行的研究的总体目标。

PROJECT ABSTRACT The proposed Bay Area Team Against Resistance U54 Project (BATAR-UP) is an interdisciplinary effort of investigators to apply their knowledge and expertise to dissect the molecular and cellular basis of incomplete response and resistance to current treatments and to identify new treatment strategies to better neutralize or eliminate residual disease and prevent resistance. This translational approach will be part of the NCI's Drug Resistance and Sensitivity Centers Network to develop innovative strategies to understand and combat mechanisms of tumor resistance and exploit tumor sensitivity to anti-cancer therapies. To accomplish this, BATAR-UP will support two projects and one core driven by a multidisciplinary team of investigators at UCSF and Stanford University. Project 1 will define and interrogate the molecular and cellular basis of residual disease in lung cancers treated with targeted inhibitors in clinical use. We will prioritize for initial study both EGFR-mutant and ALK gene rearrangement positive lung cancers, given their importance as key molecular disease subtypes and our prior published work and expertise. We will harness genetic and transcriptomic analysis of clinical samples (liquid and tumor biopsies) to provide a molecular view of the evolution of response, residual disease, and acquired resistance. We will generate organoid and PDX models and apply cutting-edge functional screens (genetic, pharmacologic, and targeted proteomic assays) to identify key vulnerabilities that could be therapeutically exploited, including with CTEP agents. This systematic approach will allow us to reveal the basis of the incomplete response and residual disease that drives EGFR and ALK inhibitor resistance and pinpoint therapeutic strategies to intercept the evolution of residual disease and eventual acquired resistance. Project 2 will define and interrogate the molecular and cellular basis of resistance and residual disease in lung cancers treated with current immunotherapies, including PD-1 and PD- L1 antibodies. Leveraging shared platforms in synergy with Project 1, we will perform systematic analyses of liquid and tumor biopsy specimens (and ex vivo models) obtained from patients longitudinally before and during treatment and upon acquired resistance. We will focus our studies on EGFR and ALK wild type patients, including squamous cell lung cancer and adenocarcinoma patients where immunotherapy has shown efficacy but is typically non-curative. We will leverage (1) a novel lung cancer organoid model wherein tumor biopsies are cultured as both tumor epithelium and their endogenous tumor infiltrating lymphocytes (TILs) en bloc as a cohesive unit, and (2) deep droplet-based single-cell RNA-seq analysis. Our systematic approach will help define the basis of the incomplete response and residual disease that contributes to immunotherapy resistance and identify potential new therapeutic strategies to help convert these incomplete responses into curative outcomes. Our Administrative Core will provide leadership, coordination and oversight for BATAR-UP with the overarching goal of synergizing the research conducted in the 2 Projects and the entire DRSC network.