SCLC Model Generation and Therapeutic Analysis

Project Summary The laboratory mouse plays a central role in the preclinical development of new therapeutic strategies and through the application of transgenic technology has proven to represent a clean genetic model to test hypotheses related to the molecular of cancer etiology. Moreover, these models are generally reliable

predictors of drug pharmacokinetics, pharmacodynamics, and efficacy in vivo. Core B proposes two Specific Aims. Specific Aim 1 will engineer human and mouse cell lines using CRISPR genome engineering to disrupt genes identified by each of the Projects, confirm loss of function through robust quality control, and distribute these cell lines to the Projects for further analysis. Somatic

genome engineering will be used to generate GEMM models that have specific genes co-mutated ab initio to test their role in treatment response, Specific Aim 2 will provide professionalized in vivo therapeutic analysis using the models already in hand or generated in the previous aim, standardizing treatment studies between

each of the Projects. These Specific Aims will bring to bear multiple cutting-edge technologies used for in vivo cancer modeling, disease monitoring by small animal imaging, pharmacodynamic analysis, and combination efficacy studies to directly test the hypotheses generated in each of the Projects.