Targeting Lung Cancer Vulnerabilities

总孢子摘要/摘要 瞄准肺癌的脆弱性。德克萨斯大学的孢子在肺癌中代表了一个独特的 德克萨斯大学西南医学中心(UTSW)与德克萨斯大学的合作 MD安德森癌症中心(MDACC)，这两个中心在肺癌翻译方面都有突出的优势 和临床研究。孢子的首要目标是开发新的治疗范例，基于 最近发现在肺癌发病过程中获得的“脆弱性”，包括一种分子 了解个别患者的肺癌情况，并利用这些信息对每个患者进行“个性化”治疗 肺癌患者。因此，我们的战略是确定肺癌的“治疗四重奏”，其中包括：1.a 具体的脆弱性；2.为脆弱性确定治疗靶点的作用机制(S)；3.a 靶点的可交付治疗(S)；以及4.预测易损性的肿瘤分子生物标志物 每个病人的治疗方法。UT肺癌孢子建立在20年的生产历史基础上，包括 我们的孢子研究人员和其他肺癌翻译研究的最新进展 肿瘤自主和微环境的分子和机制理解中的共同体 变化、获得性脆弱性和重要的免疫肿瘤学效应。这些进步包括小说 识别和分子分类肺癌代谢改变易损性的方法， 癌症免疫惰性到PD1/PD-L1关卡阻断，肺癌间质纤维化 (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老鼠模型系统，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。孢子由4个项目组成， 所有这些都有人类的终点：1.靶向肺癌的代谢易损性；2.靶向 免疫惰性肺癌中的脆弱性；3.纤维细胞外基质中的靶向脆弱性 肺癌(ECM)；和4.癌基因诱导的复制应激对肿瘤细胞杀伤的治疗性靶向 和小细胞肺癌(SCLC)的抗肿瘤免疫(包括一项针对复制的临床试验 应激与免疫检查点抑制相结合。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；C.数据科学以及STRONG 发展研究和职业提升计划(DRP、CEP)。我们的孢子特征领先于 肺癌多学科临床和实验室科学家，一批经验丰富的患者权益倡导者，以及 杰出的出版记录。下一步，这个孢子将提供关于新发现的肺部的信息 癌症获得性脆弱性，个性化患者治疗的生物标志物，以及重要的临床前研究 以及有助于临床翻译的信息，这些信息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.