Bay Area Team Against Resistance

湾区抗击队

• 批准号: 10241307
• 负责人: Trever G Bivona
• 金额: $ 114.95万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241307
• 关键词: ALK gene; Address; Area; BRAF gene; Biological Assay; Biopsy; Biopsy Specimen; Cancer Etiology; Cancer Patient; Cancer Therapy Evaluation Program; Cell Compartmentation; Chronic; Clinical; Coupled; Cytotoxic Chemotherapy; Diagnostic radiologic examination; Drug resistance; Epidermal Growth Factor Receptor; Epithelial; Evolution; Gene Rearrangement; Genes; Genetic; Genomics; Goals; Immunotherapy; Intercept; Knowledge; Leadership; Liquid substance; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of lung; Methods; Modeling; Molecular; Molecular Disease; Molecular Profiling; Molecular Target; Organoids; Outcome; Patients; Pharmacology; Proteomics; Publishing; Research; Research Personnel; Residual Tumors; Resistance; Sampling; Sea; Signal Transduction Inhibitor; Specimen; Squamous Cell Lung Carcinoma; Therapeutic; Tumor-Infiltrating Lymphocytes; Tumor-infiltrating immune cells; Universities; Work; anti-PD-1; anti-PD-L1 antibodies; anti-PD1 antibodies; base; cancer cell; cancer therapy; cohesion; combat; disorder subtype; drug sensitivity; fight against; improved; inhibitor/antagonist; innovation; mortality; multidisciplinary; mutant; novel; novel therapeutic intervention; patient derived xenograft model; patient response; prevent; programmed cell death protein 1; programs; resistance mechanism; response; sharing platform; single-cell RNA sequencing; success; synergism; targeted agent; targeted treatment; therapeutic target; transcriptomics; translational approach; treatment strategy; tumor; tumor progression; tumorigenesis

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.

项目摘要 拟议的反对抵抗U54项目（BATAR-UP）的湾区团队是跨学科的努力 研究人员运用其知识和专业知识，以剖析不完整的分子和细胞基础 对当前治疗的反应和抵抗力，并确定新的治疗策略以更好地中和或 消除残留疾病并防止抗药性。这种翻译方法将成为NCI药物的一部分 抵抗和敏感性中心网络，以制定创新策略来理解和战斗 肿瘤耐药性和利用肿瘤对抗癌疗法的敏感性。 为此，Batar-Up将支持两个项目和一个由多学科驱动的核心 UCSF和斯坦福大学的调查人员团队。项目1将定义和询问分子和 在临床用途中用靶向抑制剂治疗的肺癌中残留疾病的细胞基础。我们将优先考虑 为了初步研究EGFR突变和碱基因重排阳性肺癌，鉴于它们的重要性 作为关键分子疾病亚型以及我们先前发表的工作和专业知识。我们将利用遗传和 临床样品（液体和肿瘤活检）的转录组分析，以提供分子视图 反应，残留疾病和获得的抗性的演变。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，药理和靶向蛋白质组学测定）来鉴定 可以利用治疗的关键漏洞，包括与CTEP代理。这个系统 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 和碱性抑制剂的耐药性和精确的治疗策略，以拦截残留疾病的演变 最终获得的抵抗。项目2将定义和询问分子和细胞基础 用当前免疫疗法治疗的肺癌中的抗性和残留疾病，包括PD-1和PD- L1抗体。利用与项目1协同作用的共享平台，我们将进行系统分析 液体和肿瘤活检标本（和离体模型）在纵向和 在治疗期间和获得抵抗。我们将把研究重点放在EGFR和ALK野生型患者上， 包括鳞状细胞肺癌和免疫疗法的腺癌患者 但通常是非耐药的。我们将利用（1）一种新型的肺癌器官模型，其中肿瘤活检 被培养为肿瘤上皮及其内源性肿瘤浸润淋巴细胞（TILS）En Bloc 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 定义有助于免疫疗法的不完全反应和残留疾病的基础 并确定潜在的新治疗策略，以帮助将这些不完整的反应转化为治愈性 结果。我们的行政核心将为Batar提供领导，协调和监督 在两个项目和整个DRSC网络中进行的研究协同作用的总体目标。