Integrating Genomic and Sociobiological Data to Inform the Development of Prostate Cancer Treatment

研究项目3-项目总结 在前列腺癌的预后方面存在着相当大的和持续的种族差异。前列腺癌 不成比例地影响非洲裔美国人的发病率，发病率和死亡率，即使在 调整阶段。非裔美国人患前列腺癌的风险增加2至3倍 与白色男性相比死亡率更高。前列腺癌预后的种族差异 反映了维生素D水平的种族差异。非洲裔美国人的维生素D患病率很高 缺乏;几项研究表明，大多数非洲裔美国人的 循环维生素D因此，补充维生素D3可能对这些男性特别有益。 维生素D促进前列腺癌细胞的分化，并维持前列腺癌细胞的分化表型。 前列腺上皮细胞，提高了长期维生素D缺乏可能导致 亚临床前列腺癌进展为临床疾病，尤其是在非洲裔美国男性中。 因此，消除维生素D循环水平的种族差异可能对以下方面产生重要影响： 减少前列腺癌结果的差异。这个基于MUSC的研究团队已经表明， 补充剂消除了非洲裔美国人和白色人之间血清25（OH）D水平的种族差异 男性，每天补充4000国际单位（IU）的维生素D3可能使以下患者受益： 低风险的前列腺癌进行积极监测。研究人员计划进行一项研究， 美国和白色男性谁已被诊断为前列腺癌，并已选择前列腺切除术作为 一个决定性的治疗。这些受试者将随机接受每天4000 IU的维生素D3补充剂（或 安慰剂）两个月，然后进行手术。他们计划评估前列腺中的转录谱， 手术时从这些受试者中采集的组织标本，使用RNA测序（RNA-seq） 技术.本申请的主要目的是确定a）是否存在显著差异 在非裔美国人和白色男性之间前列腺组织样本中转录; B）维生素 与安慰剂相比，每天补充4000 IU D3两个月， c）参与前列腺组织中的转录的基因是否与前列腺组织中的转录相关; 下丘脑-垂体-肾上腺（HPA）轴在非洲人和非洲人之间的前列腺中差异表达。 美国和白色男性以及维生素D3补充剂如何影响HPA轴。比较 在治疗组或安慰剂组中招募的受试者之间的转录谱和生物学途径 这项研究还将使我们能够确定补充维生素D3是否对前列腺有益， 早期前列腺癌的预防和/或治疗选择，特别是在非洲裔美国人中 男人

RESEARCH PROJECT 3 – PROJECT SUMMARY There are considerable and persistent racial disparities in prostate cancer outcomes. Prostate cancer disproportionately affects African American men in terms of incidence, morbidity, and mortality, even after adjustment for stage. African American men have a 2- to 3- times increased risk of developing prostate cancer and have a greater mortality rate compared to white men. Racial disparities in prostate cancer outcomes mirror racial differences in vitamin D levels. African American men exhibit a high prevalence of vitamin D deficiency; several studies have shown that a majority of African American men has sub-optimal levels of circulating vitamin D. For this reason, vitamin D3 supplementation is likely to particularly benefit these men. Vitamin D promotes the differentiation of prostate cancer cells and maintains the differentiated phenotype of prostate epithelial cells, raising the possibility that long-term vitamin D deficiency may contribute to the progression of subclinical prostate cancer to clinical disease, especially among African American men. Therefore, eliminating racial disparities in circulating levels of vitamin D could have important implications for reducing disparities in prostate cancer outcomes. This MUSC-based research team has shown that supplementation eliminates racial disparities in serum levels of 25(OH)D between African American and white men, and that vitamin D3 supplementation at 4000 international units (IU) per day may benefit patients with low-risk prostate cancer on active surveillance. The investigators plan to conduct a study enrolling African American and white men who have been diagnosed with prostate cancer and have selected prostatectomy as a definitive treatment. These subjects will be randomized to vitamin D3 supplementation at 4000 IU per day (or placebo) for two months, before undergoing surgery. They plan to assess the transcription profiles in prostate tissue specimens collected from these subjects at time of surgery, using RNA sequencing (RNA-seq) technology. The main objectives of this application are to determine a) whether there are significant differences in transcription within prostate tissue specimens between African American and white men; b) whether vitamin D3 supplementation at 4000 IU per day for two months, compared to placebo, will significantly affect transcription in prostate tissue specimens from enrolled subjects; and c) whether genes involved in the hypothalamic-pituitary-adrenal (HPA) axis are differentially expressed in the prostate between African American and white men and how vitamin D3 supplementation affects the HPA axis. Comparison of transcription profiles and biological pathways between subjects enrolled in the treatment or the placebo arm of the study will also allow us to establish whether vitamin D3 supplementation is beneficial to the prostate and as a preventive and/or therapeutic option for early-stage prostate cancer, especially among African American men.