Racial Differences in Prostate Cancer Molecular Subtyping

前列腺癌分子亚型的种族差异

• 批准号: 10376281
• 负责人: Stephen Jay Freedland
• 金额: $ 39.23万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10376281
• 关键词: Affect; African American; African ancestry; 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.

非洲裔美国人（AA）男性是前列腺癌（PC）风险最高的人群之一。他们提出了 晚期疾病，并有比白人（CA）男性更差的结果。AA PC的基因组学已经被 与CA PC相比，研究严重不足。目前尚不清楚致癌途径是否在竞赛中驱动PC- 敏感的方式，以及如何针对这些途径。我们最近开发并报道了一部小说 PC的分类算法，我们认为这是一个显着的进步，比以前的方法。 我们发现，通过单独分析转录组数据，大多数PC可以被分配到三个新的基因之一， 亚型，命名为PCS 1（管腔）、PCS 2（管腔）和PCS 3（基底）。在10多个独立的 在同一队列中，PCS 1亚型表现出最差的临床结局，包括在Gleason评分低的肿瘤中 得分PCS 1和PCS 3亚型在去势抵抗性PC（CRPC）中过度表达。基因组学、 AA PC的转录组学和免疫组化研究与PCS 1的假设一致 而PCS 3亚型在非洲血统男性中出现的PC中过度表达。我们用这本小说 系统，结合其他计算和实验室方法，以确定一个发展 转录因子ONECUT 2（OC 2），其似乎在CRPC的子集中作为“主调节因子”起作用。 这种蛋白质似乎在PCS 1和PCS 3亚型中最活跃，因此可能是一种关键的蛋白质。 在AA男性中观察到的肿瘤进展介质。OC 2似乎可以用小分子靶向， 因此，在AA男性的侵袭性PC背景下，可能是一个可行的药物靶点。 在本研究中，我们将检验两个假设：假设1）PCS系统可以识别不同的分子 来自AA男性的PC的特征，可用于临床，以帮助风险分层，并确定可采取行动的 假设2）OC 2是AA男性中出现的PC中的可行药物靶标。在Aim中 1我们将1.1）确定AA男性中PC亚型的分布，并评估它们是否类似地预测AA男性中PC亚型的分布。 在AA和CA男性中进展为晚期疾病; 1.2）鉴定在AA中起作用的主调节蛋白 以及1.3）确定PCS系统的应用是否可以用于提高预测能力 癌症相关的预后信号。在目标2中，我们将开发使用根治性直肠癌切除术的方法， AA和CA男性的活检标本，以确定哪些肿瘤对OC 2靶向药物最敏感。 疗法在目标3中，我们将确定OC 2是否是可行的药物靶标。 这项研究将是有史以来在AA PC中进行的最大规模的RNA表达数据综合分析。它 将提供一个严格的测试的假设，分子机制指定基因调控和信号 在AA与CA男性中转导不同。这些研究还将评估一种新的药物靶点， 影响非洲血统男性的许多PC的核心驱动力。