Dietary Fat Modulation and Targeted Therapies for Prostate Cancer Prevention

饮食脂肪调节与前列腺癌预防的靶向治疗 使用临床前模型，我们的小组已经证明了饮食脂肪的减少和降低 Omega-6至omega-3脂肪酸对前列腺癌的发展和进展有影响。这部作品 已经转化为一项正在进行的临床试验，以确定改变饮食脂肪的数量和质量 对前列腺癌患者血清和前列腺组织营养相关、癌症相关生物标志物的影响。 根据我们临床前和临床研究的数据，我们推测， 调节膳食脂肪的抗癌作用是通过IGFBP-1介导的抑制IGF信号转导和 通过抑制COX-2依赖的PGE-2的产生。我们目前提案的主要目的是 确定IGF/IGFBP和COX-2/PGE-2通路在膳食抗癌作用中的作用 脂肪调节。我们将通过使用(1)血清和前列腺的一系列实验来实现这一点。 从前列腺癌男性正在进行的饮食脂肪干预试验中获得的组织，(2)途径- 我们建立的针对IGF的特异性和组织特异性基因改变的小鼠前列腺癌模型 和COX-2途径，将被检查饮食脂肪反应性，(3)和雄激素依赖 饮食脂肪优化联合靶向IGF治疗SCID小鼠异种移植模型 或者COX-2制药公司。我们建议的研究将转化为临床试验，测试最 饮食脂肪调节与靶向分子干预的有希望的结合，如抗体 IGF-1R或COX-2抑制剂，以评估对已定义的血清和组织生物标志物的影响。我们的整体 目标是这些研究将直接导致大规模、前瞻性的临床试验结合有针对性的 通过优化饮食脂肪来预防前列腺癌的发展和进展的治疗。

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.