Bay Area Team Against Resistance

项目摘要 拟议的湾区抗击抵抗U54小组项目(巴托-UP)是一项跨学科的努力， 研究人员将应用他们的知识和专业知识来剖析不完全的分子和细胞基础 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 消除残病，防止产生抗药性。这种翻译方法将成为NCI药物的一部分 抵抗和敏感中心网络制定了解和打击的创新战略 肿瘤耐药机制和开发肿瘤对抗癌治疗的敏感性。 为了实现这一目标，巴托-UP将支持两个项目和一个由多学科驱动的核心 加州大学旧金山分校和斯坦福大学的调查团队。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残留疾病的细胞学基础。我们将确定优先顺序 对于EGFR突变和ALK基因重排阳性肺癌的初步研究，考虑到它们的重要性 作为关键的分子疾病亚型和我们之前发表的工作和专业知识。我们将利用遗传和 对临床样本(液体和肿瘤活检)进行转录切分分析，以提供对 反应、残留疾病和获得性抵抗力的进化。我们将生成有机物和PDX模型 并应用尖端功能筛选(遗传、药理学和靶向蛋白质组分析)来识别 可以在治疗上利用的关键漏洞，包括CTEP代理。这个系统化的 方法将使我们能够揭示导致EGFR的不完全反应和残留疾病的基础 和ALK抑制剂耐药性和精准治疗策略，以拦截残留疾病的演变 并最终获得抵抗力。项目2将定义和询问分子和细胞基础 目前包括PD-1和PD-1在内的免疫疗法治疗肺癌的耐药性和残留疾病 L1抗体。在与项目1的协同中利用共享平台，我们将对 液体和肿瘤活检标本(和体外模型)从患者的纵向前和后 在治疗期间和在获得抵抗力时。我们将重点研究EGFR和ALK野生型患者， 包括免疫治疗有效的鳞状细胞肺癌和腺癌患者 但通常是不能治愈的。我们将利用(1)一种新的肺癌器官模型，在该模型中肿瘤活检 同时培养为肿瘤上皮细胞及其内源性肿瘤浸润性淋巴细胞(TIL)。 (2)基于深度液滴的单细胞RNA-seq分析。我们的系统化方法将会有所帮助 确定导致免疫治疗抵抗的不完全应答和残留疾病的基础 并确定潜在的新治疗策略，帮助将这些不完全反应转化为治愈 结果。我们的行政核心将提供领导、协调和监督 将两个项目和整个DRSc网络中进行的研究协同起来的总体目标。

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.