Animal Modeling and Preclinical Therapeutics Core in this P01 will use genetically engineered mouse (GEM) models of lung cancer, standard lung cancer cell line xenografts, and patient-derived lung cancer xenografts (PDXs) to facilitate the identification of the most effective tool compounds and combination(s) of compounds in the treatment of the genotype-specific stratified lung cancers studied in each of the projects. This core will provide technical and scientific expertise for in vivo experiments for each project in the program and allow the collective efforts of each of the three projects to focus more on the mechanistic studies to identify the best combination of compounds to maximize therapeutic efficacy. GEM models of lung cancers based on specific oncogenic genetic alterations have been instrumental in advancing the understanding of the molecular mechanisms of lung cancer pathogenesis and in the development of targeted therapeutics that are effective specific types of oncogene-driven lung cancer. Our laboratory has generated and characterized well over 30 conditional transgenic mice alleles that have inducible expression of each of the characterized lung cancer relevant oncogenic drivers. We have also created a repository of over 50 genomically annotated NSCLC lines, which can be used for conventional xenograft studies. More importantly, these GEM and standard xenograft lung cancer models have been employed successfully in multiple efficacy and pharmacodynamics studies with novel therapeutics that target genetically defined oncogenic drivers or their downstream effector pathways. In addition, our laboratory are in the process of generating and characterizing lung cancer PDX models derived from patient resected/biopsy samples at DFCI. The appropriate EGFR, KRAS, and other-genotype specific GEM, PDX and xenograft models will be used for each of the projects described in this P01 proposal. Overall the Animal Modeling and Preclinical Therapeutics Core will facilitate the preclinical discoveries that enable clinical translation with the ultimate goal of improving lung cancer outcomes.
The Animal Core (Core C) aims to use genetically engineered mouse (GEM) lung cancer models, human lung cancer cell line xenografts, and patient derived xenograft (PDX) models of lung cancer to elucidate mechanisms of lung cancer pathogenesis, to validate therapeutic targets, to determine in vivo therapeutic efficacy and to elucidate in vivo mechanisms of acquired resistance, for all three Projects in this Program. The core serves three specific purposes: a) a high-tech core and intellectual resource to perform and assist with all aspects of in vivo experiments; b) an innovative research core to develop new genetically engineered mouse models based on genetic alterations and deregulated pathways validated in vitro from all three Projects and c) generation of annotated PDX from lung cancer patients at the time of diagnosis and at time of relapse from various novel therapeutic treatments relevant to all three Projects.
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