Autochthonous Mouse Models of Cancer: Development and Use in Therapeutic Screens

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Mouse models for human cancer have been crucial to our understanding of the biology of cancer, its origins and its treatment. In this project, we describe the further development of mouse models for four epithelial tumor types, that of the colon, cervix, pancreas and breast and their use in screening novel therapeutic drugs discovered in the prior projects. The mouse models that will be used have been developed and/or characterized by the co-project leaders, Drs. Dove (colon), Lambert (cervix), Sandgren (pancreas), Alexander (breast) and Moser (colon and breast). These mouse models will be further refined in the context of the proposed studies to make them more amenable to theier use in therapeutic screens. This developmental effort will include continued assessment and refinement of tumor imaging capabilities that will allow for real time imaging of tumors before, during and after treatment of animals with candidate therapeutic drugs. The tumor imaging effort will be pursued in close collaboration with Dr. Jamey Weichert, an expert in small animal imaging here at the University of Wisconsin Comprehensive Cancer Center. Once the models are fully refined, they will be used to screen a select number of candidate drugs generated under Projects 1 and 2 that have passed tissue culture based cytotoxicity and animal based pharmakinetics screens. This drug screening will be performed together with Core C. We will not only test the efficacy of drugs in reducing tumor burden, but also characterize the histopathological effects of drug treatment on multiple parameters of the different cancer types and determine the ability of the drugs to prevent recurrence.