Racial Differences in Prostate Cancer Molecular Subtyping

前列腺癌分子亚型的种族差异

• 批准号: 10116314
• 负责人: Stephen Jay Freedland
• 金额: $ 40.03万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116314
• 关键词: Affect; African; African American; Automobile Driving; Biopsy Specimen; Castration; Caucasians; Classification; Clinical; Computing Methodologies; Data; Development; Disease; Drug Targeting; Exhibits; Family; Gene Expression Regulation; Gene Targeting; Genetic Transcription; Genomics; Gleason Grade for Prostate Cancer; Growth; Heterogeneity; Label; Laboratories; Malignant Neoplasms; Malignant neoplasm of prostate; Mediator of activation protein; Methods; Molecular; Molecular Profiling; Names; Oncogenic; Outcome; PTEN gene; Pathway interactions; Pharmaceutical Preparations; Pilot Projects; Proteins; RNA analysis; Race; Radical Prostatectomy; Reporting; Resistance; Signal Transduction; Specific qualifier value; System; Testing; Tissues; advanced disease; biophysical properties; cancer subtypes; castration resistant prostate cancer; classification algorithm; cohort; companion diagnostics; high risk; improved; men; molecular subtypes; new therapeutic target; novel; pre-clinical; precision medicine; preclinical study; prognostic signature; prostate cancer risk; racial difference; response; risk stratification; small molecule; targeted treatment; transcription factor; transcriptome; transcriptomics; tumor

African-American (AA) men exhibit one of the highest risks for prostate cancer (PC). They present with later-stage disease and have worse outcomes than Caucasian (CA) men. The genomics of AA PCs has been dramatically understudied compared to CA PCs. It is unclear whether oncogenic pathways drive PC in a race- sensitive manner, and how such pathways might be targeted. We recently developed and reported on a novel algorithm for classification of PC that we believe represents a significant advance over previous approaches. We found that by analyzing transcriptome data alone, most PCs can be assigned to one of only three novel subtypes, named PCS1 (luminal), PCS2 (luminal), and PCS3 (basal). As validated in over 10 independent cohorts, the PCS1 subtype demonstrates the worst clinical outcome, including in tumors with low Gleason score. The PCS1 and PCS3 subtypes are over-represented in castration-resistant PCs (CRPC). Genomics, transcriptomics, and immunohistochemical studies of AA PCs are consistent with the hypothesis that the PCS1 and PCS3 subtypes are over-represented in PCs arising in men of African ancestry. We have used this novel system, in combination with other computational and laboratory approaches, to identify a developmental transcription factor, ONECUT2 (OC2), which appears to operate as a “master regulator” in a subset of CRPCs. This protein appears to be most active in the PCS1 and PCS3 subtypes, and therefore may be a critical mediator of progression in tumors seen in AA men. OC2 appears targetable with a small molecule and therefore may be a viable drug target in the context of aggressive PCs in AA men. We will test two hypotheses in this study: Hypothesis 1) The PCS system can identify distinct molecular features of PCs from AA men that can be used clinically to aid risk stratification and to identify actionable targets relevant to AA men; and Hypothesis 2) OC2 is a viable drug target in PCs that arise in AA men. In Aim 1 we will 1.1) determine the distribution of PC subtypes in AA men, and assess whether they similarly predict progression to advanced disease in AA and CA men; 1.2) identify master regulator proteins operating in AA PCs; and 1.3) determine whether application of the PCS system can be used to improve the predictive power of cancer-relevant prognostic signatures. In Aim 2 we will develop methods using radical prostatectomy and biopsy specimens from AA and CA men to determine which tumors will be most sensitive to OC2-targeted therapy. In Aim 3 we will determine whether OC2 is a viable drug target. This study will be the largest integrated analysis of RNA expression data ever performed in AA PCs. It will provide a rigorous test of the hypothesis that molecular mechanisms specifying gene regulation and signal transduction differ in AA vs. CA men. These studies will also evaluate a novel drug target that appears to be a central driver of many PCs affecting men of African ancestry.

非裔美国人（AA）男性表现出前列腺癌（PC）最高风险之一。他们与之展示 后期疾病，比白人（CA）男性的结局差。 AA PC的基因组学已经 与CA PC相比，动态理解。目前尚不清楚致癌途径是否在种族中驱动PC- 敏感的方式以及如何针对此类途径。我们最近开发并报道了一本小说 我们认为，用于PC分类的算法代表了先前方法的重大进步。 我们发现，通过单独分析转录组数据，大多数PC可以分配给只有三个新颖的新型PC之一 亚型，名为PCS1（Luminal），PCS2（Luminal）和PCS3（基础）。在10多个独立中得到了验证 队列，PCS1亚型证明了最糟糕的临床结果，包括在较低的肿瘤中 分数。 PCS1和PCS3子类型在castration耐药的PC（CRPC）中代表过多。基因组学， AA PC的转录组学和免疫组织化学研究与PCS1的假设一致 PCS3亚型在非洲血统的男性中产生的PC中过高。我们使用了这本小说 系统结合其他计算和实验室方法，以确定发展性 转录因子OneCut2（OC2），在CRPC的子集中似乎是“主调节器”。 该蛋白在PCS1和PCS3亚型中似乎是最活跃的，因此可能是关键 在AA男性中看到的肿瘤进展的介体。 OC2似乎具有小分子和 因此，在AA男性的侵略性PC的背景下，可能是可行的药物靶标。 我们将在这项研究中检验两个假设：假设1）PCS系统可以识别出不同的分子 可以在临床上使用的AA男士的PC的功能，以帮助风险分层并确定可操作的 与AA男子相关的目标；假设2）OC2是AA男性出现的PC中的可行药物靶标。目标 1我们将1.1）确定AA男性中PC子类型的分布，并评估他们是否类似地预测 在AA和CA男性中发展为晚期疾病； 1.2）识别在AA中运行的主调节蛋白 件; 1.3）确定是否可以使用PCS系统的应用来提高预测能力 与癌症相关的预后特征。在AIM 2中，我们将使用根部前列腺切除术和 来自AA和CA男性的活检标本，以确定哪些肿瘤对OC2靶向最敏感 治疗。在AIM 3中，我们将确定OC2是否是可行的药物靶标。 这项研究将是对AA PC中有史以来RNA表达数据的最大综合分析。 将对指定基因调节和信号的分子机制的假设进行严格的检验 AA与CA男子的转导差异。这些研究还将评估一个新的药物靶标，这似乎是 许多影响非洲血统的人的核心驱动力。