Prevention of Prostate Cancer Progression Using Omega-3 Fatty Acids

描述(申请人提供)：去雄激素治疗转移性前列腺癌最初是有用的，但进展到雄激素非依赖性通常会导致2年内复发。目前，前列腺癌的进展到雄激素非依赖性仍然是提高这种疾病存活率的主要障碍。为了提高总体存活率，需要确定新的治疗策略，这些策略基于延长雄激素依赖状态的特定分子机制，并且对雄激素非依赖性疾病有用。流行病学和临床前数据都表明，omega-3脂肪酸是有效的主要肿瘤预防药物，但它们在预防和治疗难治性前列腺癌方面的效果尚未得到彻底的研究。作为R03的一部分产生的初步数据表明，在体外，omega-3脂肪酸能够阻止激素依赖的前列腺癌细胞向雄激素非依赖性状态发展。我们的总体假设是，必需的多不饱和脂肪酸能够调节前列腺癌进展到雄激素非依赖状态的关键遗传和表观遗传过程，并且omega-3脂肪酸和omega-6脂肪酸之间平衡的改变会导致这些过程的变化，可以有效地利用这些过程来预防难治性前列腺癌。根据我们自己的研究结果和之前发表的其他实验室的报告，我们将在这一应用中解决的具体假设是，omega-3脂肪酸调节与Akt激酶途径相关的过程，通过阻断前列腺癌细胞在雄激素缺乏期间存活并以雄激素非依赖的方式增殖的能力，阻止前列腺癌进展到激素依赖的状态。我们将通过执行以下特定目标来解决这一假说：1)确定必需多不饱和脂肪酸(PUFA)对NF-KB、COX-2和PPAR转录因子的调节如何调节对雄激素非依赖性进展至关重要的过程；2)确定mTOR激酶在调节omega-3脂肪酸中的作用；以及3)在体内研究富含omega-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的状态。将omega-3脂肪酸影响表型结果的机制联系起来，对于有效利用这些营养剂作为一种治疗方法非常重要。特定饮食成分对前列腺癌进展的影响可能取决于一系列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存活率至关重要。

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.