Targeting Lung Cancer Vulnerabilities

总体SPORE摘要/摘要 针对肺癌的脆弱性。得克萨斯大学的孢子在肺癌代表了一个独特的 德克萨斯大学西南医学中心（UTSW）和德克萨斯大学之间的合作 MD安德森癌症中心（MDACC），这两个中心在肺癌转化方面都有突出的优势， 和临床研究。SPORE的总体目标是开发基于以下方面的新治疗范例： 最近发现的"脆弱性"在肺癌发病过程中获得，包括一个分子 了解个体患者的肺癌，并使用这些信息为每个患者提供“个性化”治疗。 肺癌患者。因此，我们的策略是确定肺癌的“治疗四重奏”，其中包括：1。一 具体脆弱性; 2.作用机制，从而定义脆弱性的治疗靶点; 3.一 针对目标的可交付治疗;以及4.肿瘤分子生物标志物的脆弱性预测具体 为每位患者提供治疗。UT肺癌孢子建立在20年的生产历史上， 我们的SPORE研究人员和其他肺癌转化研究的最新进展 在肿瘤自主和微环境的分子和机制的理解社区 变化、获得性脆弱性和重要的免疫肿瘤学效应。这些进展包括新的 识别和分子分类肺癌代谢组学变化中的脆弱性的方法， 癌症对PD1/PD-L1检查点阻断免疫"惰性"，肺癌纤维化基质 （微环境）和肿瘤发生诱导的复制应激。我们的贡献还包括临床前 用于测试不同漏洞的人类和小鼠模型系统，以及大型遗留分子和 临床注释的临床前模型和临床样本数据集。SPORE由4个项目组成， 所有这些都有人类终点：1。针对肺癌的代谢脆弱性; 2.靶向 免疫惰性肺癌的脆弱性; 3.靶向纤维化细胞外基质的脆弱性 (ECM)肺癌;及4.癌基因诱导的复制应激对肿瘤细胞杀伤的靶向治疗 和小细胞肺癌（SCLC）的抗肿瘤免疫（包括针对复制的临床试验 应激与免疫检查点预防相结合。有三个核心：A.管理（包括患者 倡导者）; B.分子病理学和组织资源;和C。数据科学，以及强大的 发展研究和职业提升计划（DRP，CEP）。我们的SPORE功能领先 肺癌多学科临床和实验室科学家，一批经验丰富的患者倡导者， 杰出的出版记录展望未来，该SPORE将提供新发现的肺 癌症获得性脆弱性，个性化个体患者治疗的生物标志物，以及重要的临床前 和信息，以促进临床翻译，有可能改变肺癌治疗的面貌。

Overall SPORE Summary/Abstract Targeting Lung Cancer Vulnerabilities. The University of Texas SPORE in Lung Cancer represents a unique collaboration between the University of Texas Southwestern Medical Center (UTSW) and the University of Texas MD Anderson Cancer Center (MDACC), both of which have outstanding strengths in lung cancer translational and clinical research. The overarching goal of the SPORE is to develop new therapeutic paradigms based on recently identified “vulnerabilities” acquired during lung cancer pathogenesis, including a molecular understanding of lung cancers in individual patients, and using this information to “personalize” therapy for each lung cancer patient. Thus, our strategy is to identify lung cancer “therapeutic quartets” which include: 1. a specific vulnerability; 2. the mechanism of action thus defining therapeutic target(s) for the vulnerability; 3. a deliverable treatment for the target(s); and 4. tumor molecular biomarkers for the vulnerability predicting specific therapies for each patient. The UT Lung Cancer SPORE builds on a 20-year productive history, incorporating recent advances made by our SPORE investigators and the rest of the lung cancer translational research community in the molecular and mechanistic understanding of tumor autonomous and microenvironment changes, acquired vulnerabilities, and important immuno-oncology effects. These advances include novel approaches to identifying and molecularly classifying vulnerabilities in lung cancer metabolomic changes, cancers immunologically “inert” to PD1/PD-L1 checkpoint blockade, the lung cancer fibrotic stroma (microenvironment), and tumorigenesis-induced replication stress. Our contributions also include preclinical human and mouse model systems for testing the different vulnerabilities, as well as large legacy molecular and clinically annotated preclinical model and clinical specimen datasets. The SPORE is composed of 4 projects, all of which have Human Endpoints: 1. Targeting metabolic vulnerabilities in lung cancer; 2. Targeting vulnerabilities in immunologically-inert lung cancer; 3. Targeting vulnerabilities in the fibrotic extracellular matrix (ECM) of lung cancers; and 4. Therapeutic targeting of oncogene-induced replication stress for tumor cell killing and anti-tumor immunity in small cell lung cancer (SCLC) (which includes a clinical trial targeting replication stress combined with immune checkpoint inhibtion. There are three cores: A. Administrative (including patient advocates); B. Molecular Pathology and Tissue Resources; and C. Data Sciences, as well as strong Developmental Research and Career Enhancement Programs (DRP, CEP). Our SPORE features leading lung cancer multi-disciplinary clinical and laboratory scientists, a cadre of experienced patient advocates, and an outstanding publication record. Moving forward, this SPORE will provide information on newly identified lung cancer acquired vulnerabilities, biomarkers for personalizing individual patient therapy, and important preclinical and information to facilitate clinical translation that has the possibility of changing the face of lung cancer therapy.