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.
Lung cancer is the biggest cancer killer of men and women in the USA today and the research proposed in this SPORE seeks to harness recent advances in the molecular understanding of lung cancer pathogenesis, together with advances in clinically available chemotherapy, targeted therapy, radiation therapy, and immunotherapy, to develop new lung cancer therapies. We propose to attack multiple newly identified key vulnerabilities that lung cancers acquire during their pathogenesis that are present in tumor but not normal cells including metabolic, immunologic, microenvironmental, and replication stress vulnerabilities, and are not targets for currently available therapies. In addition, we are identifying molecular biomarkers that identify which lung cancers would be best treated by each of the new therapies to provide ?precision medicine? and, if successful, the research of this SPORE should change the face of lung cancer therapy to provide a substantial beneficial impact on the public health.
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