SRD5A2 as a Marker of Resistance to 5ARI Therapy

SRD5A2 作为 5ARI 治疗耐药的标志物

• 批准号: 10380636
• 负责人: Aria F Olumi
• 金额: $ 36.48万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10380636
• 关键词: 5 Alpha-Reductase Inhibitor; Accounting; Adult; Affect; Age; Androgens; Benign Prostatic Hypertrophy; Binding; Biological Assay; Bladder; Blood specimen; Clinical; Collaborations; DNA; DNA Binding; Development; Disease; Drug usage; Enrollment; Enzymes; Epigenetic Process; Epithelial Cells; Equilibrium; Estradiol; Estrogens; Finasteride; Frequencies; Gene Silencing; Goals; Growth; Growth and Development function; Healthcare Systems; Hormonal; Hormones; Human; Hypermethylation; Individual; Inflammation; Inflammation Mediators; Interleukin-6; Investigation; Laboratory Finding; Magnetic Resonance Imaging; Medical; Methylation; Modification; NF-kappa B; Obesity; Obstruction; Oxidoreductase; Pathway interactions; Patients; Pharmaceutical Preparations; Promoter Regions; Prostate; Prostatic; Prostatic Tissue; Proteins; Quality of life; Resistance; Resistance development; Resources; Role; SRD5A2 gene; Secondary to; Serum; Steroids; Stromal Cells; TNF gene; Techniques; Technology; Testosterone; Testosterone 5-alpha-Reductase; Time; Tissues; Transferase; Translating; Work; androgenic; base; bench to bedside; blood-based biomarker; clinically significant; cost; estrogenic; ferumoxytol; genetic signature; inhibitor; inhibitor therapy; lower urinary tract symptoms; male; men; nanoparticle; patient stratification; patient subsets; precision medicine; predictive marker; promoter; prospective; protein expression; resistance mechanism; risk stratification; therapy resistant; years of life lost

PROJECT SUMMARY: Over 90% of adult males develop lower urinary tract symptoms (LUTS) secondary to bladder outlet obstruction by age 80, rendering benign prostatic hyperplasia (BPH) the most common proliferative abnormality in humans. LUTS secondary to BPH negatively impact the quality of life of 210 million men globally, accounting for significant life years lost. In this study we propose to clinically evaluate the mechanisms of resistance to 5α-reductase inhibitor, finasteride, one of the more common drugs used to manage BPH and associated LUTS. Ongoing work in our lab has focused on steroid 5α-reductase 2 (SRD5A2, aka: 5α-reductase 2 [5AR2]), the enzyme responsible for prostatic development and growth. Our investigations have revealed that expression of SRD5A2 is variable, and in fact, 30% of men do not express SRD5A2 in prostate tissues. In previous work, we showed that somatic suppression of SRD5A2 during adulthood is dependent on epigenetic changes associated with methylation of the promoter region of the SRD5A2 gene. Our studies indicate that (1) methylation of the SRDA2 is regulated by direct binding of the DNA-methyl transferase 1 (DNMT1) protein to the SRD5A2 promoter; (2) the inflammatory mediators TNF-α, NF-kB, and IL-6 regulate DNMT1 binding and subsequent methylation of the SRD5A2 promoter region; (3) clinical conditions associated with increased inflammation, age, and obesity, are associated with decreased expression of SRD5A via epigenetic modification; (4) in the absence of prostatic SRD5A2, where androgenic pathways are blocked, alternate estrogenic pathways are upregulated, leading to an androgenic-to-estrogenic switch in the prostate gland, thus creating alternate pathways for prostatic growth. Therefore, we hypothesize that absence of SRD5A2 as a result of somatic methylation is directly responsible for lack of sensitivity to 5ARI therapy in men with BPH. To demonstrate the clinical significance of epigenetic changes to SRD5A2 and confirm its role in regulating sensitivity to 5ARI treatment, we propose the following aims: Specific Aim 1: To assess the role of 5-AR2 expression in the development of resistance to 5-ARI therapy. Specific Aim 2: To demonstrate that SRD5A2 methylation turns on estrogen pathways and affects sensitivity to 5ARI therapies in men with BPH. Specific Aim 3: To determine that prostatic inflammation is associated with methylation of SRD5A2 promoter. Our findings have broad implications for the development of predictive biomarker assays that can be used to evaluate resistance to BPH-related therapies and allow clinicians to select alternate therapies for managing the most common proliferative disorder affecting men worldwide.

项目总结： 超过90%的成年男性出现继发于膀胱出口梗阻的下尿路症状(LUTS) 到80岁时，使良性前列腺增生症(BPH)成为人类最常见的增生性异常。 继发于BPH的LUTS对全球2.1亿男性的生活质量产生了负面影响，占显著比例 失去的生命年数。在本研究中，我们建议对5-α-还原酶耐药机制进行临床评估。 抑制剂，非那雄胺，是用于治疗BPH和相关的LUT的较常见药物之一。 我们实验室正在进行的工作主要集中在类固醇5α还原酶2(SRD5A2，又名：5α还原酶2[5AR2])，即 负责前列腺发育和生长的酶。我们的调查显示， SRD5A2是可变的，事实上，30%的男性在前列腺组织中不表达SRD5A2。在以前的工作中，我们 表明SRD5A2在成年期的躯体抑制依赖于表观遗传变化 与SRD5A2基因启动子区甲基化有关。我们的研究表明：(1) SRDA2的甲基化是由DNA甲基转移酶1(DNMT1)蛋白直接结合到 (2)炎症介质肿瘤坏死因子-α、核因子-kB和白介素6调节DNMT1结合和 SRD5A2启动子区域随后的甲基化；(3)与 炎症、年龄和肥胖通过表观遗传学与SRD5A表达减少相关 修饰；(4)在没有前列腺SRD5A2的情况下，其中雄激素途径被阻断，替代 雌激素途径被上调，导致前列腺癌从雄激素到雌激素的转换，因此 为前列腺生长创造了另一种途径。因此，我们假设SRD5A2的缺失是一种 体细胞甲基化的结果直接导致男性患者对5ARI治疗不敏感 前列腺增生症。目的：阐明SRD5A2基因表观遗传学改变的临床意义，并确定其在 调节对5ARI治疗的敏感性，我们提出了以下目标：具体目标1：评估 5-AR2在5-ARI治疗耐药中的表达。具体目标2：证明 SRD5A2甲基化启动雌激素通路，影响男性BPH患者对5ARI治疗的敏感性。 特异目的3：确定前列腺炎与SRD5A2启动子甲基化有关。 我们的发现对开发可用于预测的生物标记物分析具有广泛的意义 评估对BPH相关疗法的抵抗力，并允许临床医生选择替代疗法来管理 影响全球男性的最常见的增殖性疾病。