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

研究项目3--项目总结 前列腺癌患者的预后存在相当大且持续的种族差异。前列腺癌 在发病率、发病率和死亡率方面对非裔美国人男性的影响不成比例，即使在 针对阶段进行调整。非裔美国男性罹患前列腺癌的风险增加2至3倍 与白人男性相比，他们的死亡率更高。前列腺癌预后的种族差异 这反映了维生素D水平的种族差异。非洲裔美国男性维生素D的高患病率 缺乏；一些研究表明，大多数非裔美国人男性的 循环中的维生素D。因此，补充维生素D3可能对这些男性特别有益。 维生素D促进前列腺癌细胞分化并维持其分化表型 前列腺上皮细胞，增加了长期缺乏维生素D可能导致 亚临床前列腺癌向临床疾病的进展，特别是在非裔美国男性中。 因此，消除循环中维生素D水平的种族差异可能对 缩小前列腺癌结果的差异。这个以南加州大学为基础的研究团队已经表明 补充剂消除非裔美国人和白人之间血清25(OH)D水平的种族差异 每天补充4000国际单位(IU)的维生素D3可能会使患有 积极监测低风险前列腺癌。调查人员计划进行一项招收非洲人的研究 被诊断出患有前列腺癌并选择前列腺癌切除术的美国和白人男性 明确的治疗方法。这些受试者将被随机给予维生素D3补充剂，每天4000国际单位(或 安慰剂)治疗两个月，然后接受手术。他们计划评估前列腺中的转录图谱 手术时采集的组织标本，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 在非裔美国人和白人男性之间的前列腺组织样本中转录；b)维生素 与安慰剂相比，连续两个月每天补充4000IU的D3将显著影响 来自登记受试者的前列腺组织样本中的转录；以及c)参与 下丘脑-垂体-肾上腺(HPA)轴在非洲人前列腺中的差异表达 以及补充维生素D3如何影响HPA轴。比较 接受治疗的受试者和安慰剂组受试者之间的转录图谱和生物通路 这项研究还将使我们能够确定补充维生素D3是否对前列腺和AS有益 早期前列腺癌的预防和/或治疗选择，特别是在非裔美国人中 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.