Dietary Fat Modulation and Targeted Therapies for Prostate Cancer PreventionUsing pre-clinical models, our group has demonstrated that dietary fat reduction and decreasing the ratio ofomega-6 to omega-3 fatty acids impacts on the development and progression of prostate cancer. This workhas been translated into an ongoing clinical trial to determine if altering quantity and quality of dietary fateffects 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 underlyingthe anticancer effect of modulating dietary fat are through IGFBP-1-mediated inhibition of IGF signalling andthrough suppression of COX-2-dependent PGE-2 production. The primary aim of our present proposal is todetermine the contribution of the IGF/IGFBP and COX-2/PGE-2 pathways to the anticancer effect of dietaryfat modulation. We will accomplish this through a series of experiments utilizing (1) serum and prostatetissue 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 IGFand COX-2 pathways that will be examined for dietary fat-responsiveness, (3) and androgen-dependentxenograft models in SCID mice that will be treated with dietary fat optimization combined with targeted IGFor COX-2 pharmaceuticals. Our proposed studies will be translated to a clinical trial testing the mostpromising combination of dietary fat modulation with a targeted molecular intervention, such as an antibodyto the IGF-1R or a COX-2 inhibitor, to evaluate effects on defined serum and tissue biomarkers. Our overallgoal is that these studies will lead directly to large scale, prospective clinical trials combining targetedtherapies with optimization of dietary fat to prevent the development and progression of prostate cancer.
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