Dietary Fat Modulation and Targeted Therapies for Prostate Cancer Prevention

饮食脂肪调节和前列腺癌预防的靶向治疗 使用临床前模型，我们的研究小组已经证明，减少膳食脂肪和降低脂肪含量的比例 ω-6至ω-3脂肪酸对前列腺癌的发展和进展有影响。这项工作 已经转化为正在进行的临床试验，以确定是否改变饮食脂肪的数量和质量， 影响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。 根据我们的临床前和临床研究数据，我们假设两个主要机制， 调节膳食脂肪抗癌作用是通过IGFBP-1介导的IGF信号传导的抑制， 通过抑制考克斯-2依赖性PGE-2的产生。我们目前建议的主要目的是 确定IGF/IGFBP和考克斯-2/PGE-2途径对膳食纤维抗癌作用的贡献。 脂肪调制我们将通过一系列实验来实现这一点，这些实验利用（1）血清和前列腺 从正在进行的饮食脂肪干预试验中获得的前列腺癌患者的组织，（2）途径- 我们开发的靶向IGF的特异性和组织特异性遗传改变的小鼠前列腺癌模型 和考克斯-2途径，将检查饮食脂肪反应性，（3）和雄激素依赖性 SCID小鼠中的异种移植物模型，其将用膳食脂肪优化与靶向IGF组合治疗 或考克斯-2药物。我们提议的研究将转化为临床试验， 饮食脂肪调节与靶向分子干预（如抗体）的有希望的组合 IGF-1 R或考克斯-2抑制剂，以评价对确定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的前瞻性临床试验， 通过优化饮食脂肪来预防前列腺癌的发展和进展。

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.