Abstract SY22-01: Interrogating gene expression programs from preclinical analyses of genetically engineered mouse models

Our laboratories have been investigating novel mechanisms of cancer progression, as well as new therapeutic approaches for early intervention and treatment of advanced disease by integrating analyses of human clinical data with molecular and functional studies of genetically engineered mutant (GEM) mice. In our analyses of prostate cancer, we have generated GEM mice that recapitulate the entire spectrum of disease progression from preinvasive lesions, termed prostate intraepithelial neoplasia (PIN), to castration-resistant and metastatic disease, which are the lethal forms of the disease. These GEM models are based on perturbation of the Akt/mTOR and MAP kinase signaling pathways, which are often co-activated in human prostate cancer and which function synergistically to promote castration-resistant metastatic prostate cancer. We have found that combinatorial inhibition of these signaling pathways in GEM mice that display castration-resistant metastatic prostate cancer results in abrogation of primary tumors, improved survival and reduced metastasis. Using computational approaches for comparative analyses of large-scale gene expression profiling data for mouse and human prostate cancer, we have been assembling molecular networks, called interactomes, to elucidate conserved cancer pathways. We have been investigating the consequences of drugs perturbations on the transcriptional network with the ultimate goal of identifying new druggable targets. In summary, our comparative investigations of prostate cancer in humans and GEM mice have revealed promising new molecular targets and new therapuetic approaches for the treatment of human cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY22-01. doi:10.1158/1538-7445.AM2011-SY22-01