Our proposal is focused on improving treatment options for men with advanced prostate cancer through investigative research. We have been developed a novel experimental paradigm, which combines preclinical analyses in genetically-engineered mouse (GEM) models of castration-resistant prostate cancer with sophisticated cross-species computational analyses to identify master regulators of drug response. We will apply this strategy to study Abiraterone, which is an inhibitor of androgen biosynthesis that has been shown to improve survival of men with advanced prostate cancer. However, although Abiraterone has shown promising results in clinical trials, not all patients respond to Abiraterone and most of those who do respond initially eventually fail treatment. Therefore, there is a critica need to pursue preclinical investigations to understand the mechanisms of action of Abiraterone in specific tumor contexts, and to define biomarkers predictive of response and resistance. Toward this end, our studies will focus on the following critical questions: (Aim 1): In which tumor contexts is Abiraterone responsive? We will perform preclinical studies using our GEM models, with the goal of identifying responsive and non-responsive tumors. Using gene expression signatures from these responsive and non-responsive tumors, we will perform cross-species computational analyses to identify master regulators that predict response to Abiraterone. Candidate master regulators will be validated to human prostate cancer, as well as to assess their functional relevance for response to Abiraterone in vivo. The goal of these studies is to elucidate mechanisms of Abiraterone response and biomarkers that predict its efficacy. (Aim 2): Can the efficacy of Abiraterone be improved by co-targeting with anti-androgens? We will perform preclinical studies in GEM models to evaluate the efficacy of Abireratone in combination with the anti-androgen, MDV3100. Using molecular signatures from mice treated with the individual versus combinatorial agents, we will identify master regulators that inform on the mechanisms of the drug interaction and as biomarkers of multi-drug response. Candidate master regulators will be validated to human prostate cancer, as well as in functional studies to asses their efficacy for drug action in vivo. The goal of these studies is to inform on mechanisms underlying the interaction of Abiraterone and anti-androgens, and to identify biomarkers of multi-drug response. (Aim 3): Why does treatment with Abiraterone fail? Considering mechanisms of intrinsic versus acquired resistance, we will establish GEM models that are resistant to Abiraterone treatment. Using molecular signatures from mice prior to or immediately following Abiraterone treatment or following tumor recurrence, we will identify master regulators of drug resistance. These will be validated to human prostate cancer, and to assess their ability to affect resistance to drug treatment. The goal of these studies is to eludicate mechanisms of Abiraterone resistance, and to identify biomarkers of resistance.