Dietary Fat Modulation and Targeted Therapies for Prostate Cancer Prevention Using pre-clinical models, our group has demonstrated that dietary fat reduction and decreasing the ratio of omega-6 to omega-3 fatty acids impacts on the development and progression of prostate cancer. This work has been translated into an ongoing clinical trial to determine if altering quantity and quality of dietary fat effects serum and prostate tissue nutrition-related, cancer-relevant biomarkers in men with prostate cancer. Based on data from our preclinical and clinical studies we postulate that the two main mechanisms underlying the anticancer effect of modulating dietary fat are through IGFBP-1-mediated inhibition of IGF signalling and through suppression of COX-2-dependent PGE-2 production. The primary aim of our present proposal is to determine the contribution of the IGF/IGFBP and COX-2/PGE-2 pathways to the anticancer effect of dietary fat modulation. We will accomplish this through a series of experiments utilizing (1) serum and prostate tissue obtained from an ongoing dietary-fat intervention trial in men with prostate cancer, (2) pathway- specific and tissue-specific genetically altered mouse prostate cancer models we developed targeting the IGF and COX-2 pathways that will be examined for dietary fat-responsiveness, (3) and androgen-dependent xenograft models in SCID mice that will be treated with dietary fat optimization combined with targeted IGF or COX-2 pharmaceuticals. Our proposed studies will be translated to a clinical trial testing the most promising combination of dietary fat modulation with a targeted molecular intervention, such as an antibody to the IGF-1R or a COX-2 inhibitor, to evaluate effects on defined serum and tissue biomarkers. Our overall goal is that these studies will lead directly to large scale, prospective clinical trials combining targeted therapies with optimization of dietary fat to prevent the development and progression of prostate cancer.