Prevention of Prostate Cancer Progression Using Omega-3 Fatty Acids

使用 Omega-3 脂肪酸预防前列腺癌进展

• 批准号: 7765216
• 负责人: LINDA A DEGRAFFENRIED
• 金额: $ 28.43万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7765216
• 关键词: Ablation; Address; Affect; Androgens; Animal Model; Apoptotic; Arachidonic Acids; Breast; Cells; Clinical Data; Data; Dependence; Development; Diet; Dietary Component; Dietary Intervention; Disease; Docosahexaenoic Acids; Eicosapentaenoic Acid; Epidemiology; Epigenetic Process; Equilibrium; Exposure to; Failure; Family; Fatty Acids; Gene Expression; Genes; Genetic; Growth; Growth Factor; Hormones; In Vitro; Institutes; Intake; Intervention; LNCaP; Laboratories; Link; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Molecular; Nutrient; Omega-3 Fatty Acids; Omega-6 Fatty Acids; Outcome; PC3 cell line; PPAR Pathway; PTGS2 gene; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Phosphotransferases; Polyunsaturated Fatty Acids; Prevention; Primary Neoplasm; Process; Proliferating; Property; Prostate; Prostatic Neoplasms; Publishing; Refractory; Refractory Disease; Regulation; Relapse; Reporting; Research Personnel; Role; Signal Transduction; Signal Transduction Pathway; Signaling Pathway Gene; Staging; Therapeutic; Transducers; Withdrawal; Work; base; cancer cell; cell growth; deprivation; hormone therapy; human FRAP1 protein; improved; in vivo; mTOR inhibition; neoplastic cell; novel; pre-clinical; prevent; programs; response; sensor; transcription factor; treatment strategy; tumor; tumor progression

DESCRIPTION (provided by applicant): Androgen deprivation therapies for metastatic prostate cancer are useful initially, but progression to androgen independence usually results in relapse within 2 years. Currently, progression of prostate cancer to androgen independence remains the primary obstacle to improved survival with this disease. In order to improve overall survival, novel treatment strategies that are based upon specific molecular mechanisms that prolong the androgen-dependent state and that are useful for androgen-independent disease need to be identified. Both epidemiological as well as pre-clinical data suggest that omega-3 fatty acids are effective primary tumor prevention agents, however their efficacy at preventing and treating refractory prostate cancer has not been as thoroughly investigated. Preliminary data that was generated as part of an R03 suggest that in vitro, omega-3 fatty acids are able to prevent the progression of hormone-dependent prostate cancer cells to the androgen-independent state. Our overall hypothesis is that essential polyunsaturated fatty acids are able to modulate genetic and epigenetic processes critical for prostate cancer progression to an androgen independent state, and that alteration in the balance between omega-3 fatty acids and omega-6 fatty acids results in changes to these processes that can be effectively exploited for the prevention of refractory prostate cancer. Based upon the results of our own studies and previously published reports from other laboratories, the specific hypothesis that we will address in this application is that omega-3 fatty acid modulation of processes that are linked to the Akt kinase pathway prevents prostate cancer progression to a state of hormone independence by precluding the ability of prostate cancer cells to survive during androgen deprivation and proliferate in an androgen-independent manner. We will address this hypotheses by performing the following Specific Aims: 1) To determine how essential polyunsaturated fatty acid (PUFA) regulation of NF-KB, COX-2 and PPAR transcription factors, all linked to the Akt kinase pathway, modulates processes critical for the progression to androgen independence; 2) To determine the role of the mTOR kinase in modulating omega-3 fatty acid inhibition of prostate cancer progression to androgen independence; and finally 3) To investigate in vivo whether a diet enriched for omega-3 fatty acids can inhibit prostate cancer progression to a condition of hormone independence. Connecting the mechanisms by which omega- 3 fatty acids affect phenotypic outcome is important for effective exploitation of these nutrient agents as a therapeutic approach. The impact of specific dietary components on prostate cancer progression likely depends on a host of genetic and epigenetic processes. Understanding these processes is critical for the development of effective dietary intervention strategies that improve overall survival.

描述（由申请人提供）：雄激素剥夺治疗转移性前列腺癌最初是有用的，但进展为雄激素非依赖性通常会导致2年内复发。目前，前列腺癌进展为雄激素非依赖性仍然是改善这种疾病生存的主要障碍。为了提高总生存率，需要确定基于延长雄激素依赖性状态的特定分子机制和对雄激素非依赖性疾病有用的新治疗策略。流行病学和临床前数据均表明，ω-3脂肪酸是有效的主要肿瘤预防剂，但其预防和治疗难治性前列腺癌的功效尚未得到彻底研究。作为R 03的一部分产生的初步数据表明，在体外，ω-3脂肪酸能够阻止依赖于前列腺癌细胞向雄激素非依赖性状态的进展。我们的总体假设是，必需多不饱和脂肪酸能够调节对前列腺癌进展到雄激素非依赖性状态至关重要的遗传和表观遗传过程，并且ω-3脂肪酸和ω-6脂肪酸之间平衡的改变导致这些过程的变化，这些过程可以有效地用于预防难治性前列腺癌。根据我们自己的研究结果和其他实验室先前发表的报告，我们在本申请中将提出的具体假设是，与Akt激酶途径相关的过程的ω-3脂肪酸调节通过排除前列腺癌细胞在雄激素剥夺期间存活和在雄激素缺乏时增殖的能力来防止前列腺癌进展到激素非依赖性状态，独立的方式。1）确定NF-κ B、考克斯-2和PPAR转录因子的必需多不饱和脂肪酸（PUFA）调节如何调节雄激素非依赖性进展的关键过程，所有这些转录因子都与Akt激酶途径相关; 2）确定mTOR激酶在调节ω-3脂肪酸抑制前列腺癌进展至雄激素非依赖性中的作用;以及最后3）在体内研究富含ω-3脂肪酸的饮食是否可以抑制前列腺癌进展到激素非依赖性的状况。连接ω-3脂肪酸影响表型结果的机制对于有效利用这些营养剂作为治疗方法是重要的。特定饮食成分对前列腺癌进展的影响可能取决于许多遗传和表观遗传过程。了解这些过程对于制定有效的饮食干预策略以提高总体生存率至关重要。