? Human cancer is comprised of a broad spectrum of phenotypes, based in part on the tissue of origin of the tumor. While cancer phenotypes are diverse, cancer biology has converged on shared pathways and molecular mechanisms of transformation among all tumor types. A multidisciplinary approach to defining promising molecular targets in selected pathways will utilize sophisticated mouse models in combination with bioinformatic integration of high throughput data from systems technology in order to drive discovery. ? ? Three established investigators Gilliland, Korsmeyer and Orkin, committed to mouse models of human cancer, are thematically aligned in this MMHCC proposal by the shared belief that interrogating mouse genetic models of cancer pathways will define unanticipated targets. Multiple shared interests are noted in each project at the intersections of tyrosine kinase, cell death, transcription and tumor suppressor pathways of oncogenesis. Existing or newly developed mouse models will be validated as accurate models of human cancer. The unique component of this application is to use genome wide techniques to further probe these models in order to identify resulting networks of genes and proteins that will provide new targets. Multiple high throughput assay systems will be developed within the context of the Center for Systems Biology (CSB) at DFCI. Marc Vidal, a leader in the emerging field of systems biology and a full participant of the applicant group, will enable transcriptome, proteome-interactome, and phenome profiles to create correlation maps, representing functional gene networks. The goal of this MMHCC proposal is to use these systems approaches to identify and then credential the most promising molecular targets within each cancer pathway. ? ? All investigators are committed to sharing resources and data with other members of the MMHCC and to the broader scientific community. ? ?
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