Project 1: Epigenetic variations associated with aggressiveness in prostate cancer among Puerto Rican men

项目 1：表观遗传变异与波多黎各男性前列腺癌的侵袭性相关

• 批准号: 10762081
• 负责人: Jong Y. Park
• 金额: $ 19.23万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-24 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10762081
• 关键词: Address; Admixture; Affect; Aftercare; Androgen Receptor; Automobile Driving; Biological Markers; Black Populations; Black race; Blood specimen; Cancer Center; Cancer Patient; Castration; Cell Line; Cells; Cessation of life; DNA Methylation; DNA Methylation Inhibition; Data; Development; Disease Progression; Disparity; Drug Modelings; Drug resistance; Drug usage; Epigenetic Process; Failure; Florida; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Goals; Health Sciences; Hispanic; Hispanic Populations; Incidence; Indolent; Latino; Latino Population; Malignant Neoplasms; Malignant neoplasm of prostate; Methylation; Molecular; Molecular Probes; Not Hispanic or Latino; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Play; Population; Populations at Risk; Prediction of Response to Therapy; Prostate; Prostate Cancer therapy; Puerto Rican; Reporting; Research Project Grants; Resistance; Risk; Role; Sampling; Selection for Treatments; Series; Socioeconomic Status; The Cancer Genome Atlas; Tissues; Treatment Failure; Tumor Biology; Universities; Validation; Work; androgen deprivation therapy; biobank; black men; cancer health disparity; cancer initiation; cancer type; chemotherapy; clinical risk; clinically relevant; cohort; data registry; differential expression; disease phenotype; docetaxel; drug sensitivity; enzalutamide; epigenetic variation; gene therapy; health care availability; high risk; improved; liquid biopsy; men; methylation biomarker; methylation pattern; mortality; neoplasm registry; novel; outcome disparities; patient oriented; potential biomarker; prostate cancer cell line; racial disparity; racial population; response; risk stratification; targeted agent; taxane; therapy resistant; treatment response; tumor; tumor DNA

ABSTRACT | FULL RESEARCH PROJECT 1 Puerto Rican (PR) Hispanic/Latino (H/L) men have the highest prostate cancer (PCa) mortality among Hispanic populations. According to the recent PR Cancer Registry data, PCa is the leading cancer type in terms of incidence (35% of all cancer cases) and mortality (17% of all cancer deaths) in PR H/L men. They have significantly higher PCa-specific mortality than non-Hispanic white (NHW) and non-Hispanic Black (NHB) men; addressing this gap constitutes our central efforts. While socioeconomic status and access to healthcare are contributors, manifest differences in molecular features between racial groups highlight the role of tumor biology in racially disparate outcomes in PCa. Our long-term goal is to identify DNA methylation biomarkers driving gene expression changes that underly PCa therapy resistance and aggressiveness in at-risk populations, particularly PR H/L men. The central hypothesis is that differences in tumor DNA methylation patterns and population admixture are associated with drug response and aggressiveness in PCa in PR H/L men. The rationale is that identifying the molecular basis of PCa disparities will serve to reduce the burden of lethal PCa disparities affecting PR H/L men. Our goals will be accomplished through two Specific Aims: Aim 1) Investigate associations between aggressiveness and methylated genes in PCa among the PR H/L population and the impact of methylation on their expression. (1a) Investigate differentially methylated genes associated with drug resistance and aggressiveness among PR H/L PCa patients and compare with methylation data from NHB from the Florida PCa biobank, NHW PCa patients from MCC, and TCGA. (1b) Evaluate differential DNA methylation on gene expression patterns. We will establish comparisons with previous data obtained from NHW men from MCC and TCGA. (1c) Evaluate whether population admixture will modify the methylation level of PR-specific methylated genes. Further, we will investigate whether genes that contain ancestry determinants are associated with the aggressiveness of PCa and disparity. Aim 2. Assess the contribution of DNA methylation to PCa resistance to standard therapies using drug-resistant PCa sublines and liquid biopsies from PCa patients progressing after treatment. (2a) Identify differentially methylated genes associated with drug-resistant phenotypes using cell- based models of drug resistance including castration resistance, enzalutamide resistance, and docetaxel resistance. (2b) Evaluate the expression of differentially methylated genes in resistant sublines compared to sensitive cell lines. (2c) Assess the effect of DNA methylation inhibition on drug sensitivity in resistant phenotypes. (2d) As an exploratory aim, we will evaluate resistance-associated methylation profiles in blood samples from PR and MCC patients previously treated with androgen deprivation therapy, androgen receptor- targeting agents, or taxane-based chemotherapy. The identification and validation of novel DNA methylation signatures associated with aggressive and drug-resistant PCa in PR men have the potential to improve risk stratification and treatment selection in this high-risk, understudied population.

摘要 |完整的研究项目 1 波多黎各 (PR) 西班牙裔/拉丁裔 (H/L) 男性的前列腺癌 (PCa) 死亡率在西班牙裔中最高 人口。根据最近的 PR 癌症登记数据，PCa 是主要的癌症类型 PR H/L 男性的发病率（占所有癌症病例的 35%）和死亡率（占所有癌症死亡的 17%）。他们有 PCa 特异性死亡率显着高于非西班牙裔白人 (NHW) 和非西班牙裔黑人 (NHB) 男性； 解决这一差距是我们的核心工作。虽然社会经济地位和获得医疗保健的机会 贡献者，种族群体之间分子特征的明显差异凸显了肿瘤生物学的作用 PCa 的种族差异结果。我们的长期目标是识别驱动基因的 DNA 甲基化生物标志物 表达变化是高危人群中 PCa 治疗耐药性和侵袭性的基础，特别是 PR H/L 男士。中心假设是肿瘤 DNA 甲基化模式和人群的差异 混合物与 PR H/L 男性 PCa 的药物反应和侵袭性相关。理由是 确定 PCa 差异的分子基础将有助于减轻致命的 PCa 差异的负担 PR H/L 男士。我们的目标将通过两个具体目标来实现： 目标 1) 调查之间的关联 PR H/L 人群中 PCa 的侵袭性和甲基化基因以及甲基化对 他们的表达。 (1a) 研究与耐药性相关的差异甲基化基因 PR H/L PCa 患者的侵袭性并与来自佛罗里达州 PCa 的 NHB 的甲基化数据进行比较 生物库、来自 MCC 的 NHW PCa 患者和 TCGA。 (1b) 评估基因上的差异 DNA 甲基化 表达模式。我们将与以前从 MCC 的 NHW 男性获得的数据进行比较 TCGA。 (1c) 评估群体混合是否会改变 PR 特异性甲基化的甲基化水平 基因。此外，我们将研究包含祖先决定因素的基因是否与 PCa 的侵袭性和差异。目标 2. 评估 DNA 甲基化对 PCa 耐药性的贡献 使用耐药 PCa 亚系和 PCa 患者液体活检的标准疗法 治疗。 (2a) 使用细胞识别与耐药表型相关的差异甲基化基因 基于耐药模型，包括去势耐药、恩杂鲁胺耐药和多西紫杉醇 反抗。 (2b) 与相比，评估抗性亚系中差异甲基化基因的表达 敏感细胞系。 (2c) 评估 DNA 甲基化抑制对耐药患者药物敏感性的影响 表型。 (2d) 作为探索性目标，我们将评估血液中与耐药性相关的甲基化谱 来自先前接受雄激素剥夺疗法、雄激素受体-治疗的 PR 和 MCC 患者的样本 靶向药物或基于紫杉烷的化疗。新型DNA甲基化的鉴定和验证 PR 男性中与侵袭性和耐药性 PCa 相关的特征有可能提高风险 对这一高风险、研究不足的人群进行分层和治疗选择。