Dietary Fat Modulation and Targeted Therapies for Prostate Cancer Prevention

预防前列腺癌的膳食脂肪调节和靶向治疗

基本信息

批准号：
7315072
负责人：
WILLIAM J ARONSON
金额：
$ 19.22万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-01 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7315072
关键词：
Address Affect Androgens Animals Antibodies Biochemical Biological Biological Markers Cancer Model Clinical Research Clinical Trials Data Development Diet Dietary Fats Dietary Intervention Enrollment Fat-Restricted Diet Fatty acid glycerol esters Fish Oils Future Genetic Goals Human IGF1R gene Individual Insulin-Like Growth-Factor Binding Protein 1 Intake Intervention Intervention Trial Knock-out Lead Malignant neoplasm of prostate Mediating Molecular Target Mus Omega-3 Fatty Acids PTEN gene PTGS2 gene Pathway interactions Patients Pharmacologic Substance Pre-Clinical Model Prevention Production Prostate Prostatic Intraepithelial Neoplasias Prostatic Tissue Radical Prostatectomy Randomized Controlled Clinical Trials Recurrence Research Personnel Risk SCID Mice Series Serum Signal Transduction Somatomedins Specimen Testing Tissues Translating Translations Treatment Efficacy Treatment Protocols Week Work Xenograft Model Xenograft procedure base design dietary supplements improved inhibitor/antagonist men mouse model nutrition related cancer pre-clinical preclinical study prevent prevention clinical trial programs prospective prostate cancer prevention research study response tumor progression

项目摘要

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.

预防前列腺癌的膳食脂肪调节和靶向治疗使用临床前模型，我们的团队已经证明，膳食脂肪的减少和脂肪比例的降低 omega-6 至 omega-3 脂肪酸对前列腺癌的发生和进展有影响。这部作品已转化为一项正在进行的临床试验，以确定是否改变膳食脂肪的数量和质量影响前列腺癌男性的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的数据，我们假设潜在的两种主要机制调节膳食脂肪的抗癌作用是通过 IGFBP-1 介导的 IGF 信号传导抑制来实现的通过抑制 COX-2 依赖性 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 途径对饮食抗癌作用的贡献脂肪调节。我们将通过一系列利用 (1) 血清和前列腺的实验来实现这一目标从正在进行的前列腺癌男性饮食脂肪干预试验中获得的组织，（2）途径- 我们开发的针对 IGF 的特异性和组织特异性基因改造小鼠前列腺癌模型和 COX-2 途径，将检查饮食脂肪反应性，(3) 和雄激素依赖性 SCID 小鼠异种移植模型将接受膳食脂肪优化结合靶向 IGF 治疗或 COX-2 药物。我们提出的研究将转化为临床试验，测试最膳食脂肪调节与抗体等靶向分子干预相结合的前景看好 IGF-1R 或 COX-2 抑制剂，以评估对特定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生和进展的疗法。