SRD5A2 as a Marker of Resistance to 5ARI Therapy

SRD5A2 作为 5ARI 治疗耐药的标志物

• 批准号: 10599963
• 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/10599963
• 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; 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; 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.

项目摘要： 超过90％的成年男性出现较低的尿路症状（LUTS）继发于膀胱出口障碍物 到80岁时，良性前列腺增生（BPH）是人类最常见的增生异常。 BPH继发于全球2.1亿人的生活质量的LUTS，造成了重大影响 丧生的生活。在这项研究中，我们建议在临床上评估5α-还原酶抗性的机制 抑制剂，非那雄胺是用于管理BPH和相关LUTS的最常见药物之一。 我们实验室中正在进行的工作集中在类固醇5α-还原酶2（SRD5A2，aka：5α-还原酶2 [5AR2]）上， 负责前列腺发展和增长的酶。我们的投资揭示了表达 SRD5A2是可变的，实际上，30％的男性在前列腺组织中不表达SRD5A2。在以前的工作中，我们 表明在成年期间的体细胞抑制SRD5A2取决于表观遗传变化 与SRD5A2基因的启动子区域的甲基化有关。我们的研究表明（1） SRDA2的甲基化通过DNA-甲基转移酶1（DNMT1）蛋白与与 SRD5A2启动子； （2）炎症介质TNF-α，NF-KB和IL-6调节DNMT1结合和 随后的SRD5A2启动子区域的甲基化； （3）与增加有关的临床状况 炎症，年龄和肥胖与通过表观遗传学降低SRD5A的表达有关 修改; （4）在没有前列腺SRD5A2的情况下，雄激素途径被阻塞，替代 雌激素途径被上调，导致前列腺中的雄激素到雌激素开关，因此 为前列腺增长创造替代途径。因此，我们假设不存在SRD5A2作为一个 躯体甲基化的结果直接导致对患有5ARI治疗的敏感性 BPH。证明表观遗传变化对SRD5A2的临床意义，并确认其在 调节对5ARI治疗的敏感性，我们提出以下目的：特定目的1：评估的作用 5-AR2表达在对5-ARI疗法的抗性发展中。特定目的2：证明 SRD5A2甲基化开启雌激素途径，并影响BPH男性5ARI疗法的敏感性。 特定目的3：确定前列腺炎症与SRD5A2启动子的甲基化有关。 我们的发现对预测生物标志物测定法的开发具有广泛的影响 评估对BPH相关疗法的抗药性，并允许临床医生选择替代疗法来管理 最常见的增生障碍影响全世界男性。

项目成果

High Real-World Medication Adherence and Durable Clinical Benefit in Medicare Patients Treated with 5-Alpha Reductase Inhibitors for Benign Prostatic Hyperplasia.

• DOI: 10.1097/ju.0000000000001014
• 发表时间: 2020-08
• 期刊: The Journal of urology
• 作者: Zhang H;Frendl DM;Wang Z;Olumi AF
• 通讯作者: Olumi AF

Reply by Authors.

作者回复。

• DOI: 10.1097/ju.0000000000003038.02
• 发表时间: 2023
• 期刊: The Journal of urology
• 作者: Schweizer,MichaelT;True,Lawrence;Gulati,Roman;Zhao,Yibai;Ellis,William;Schade,George;Montgomery,Bruce;Goyal,Sonia;Nega,Katie;Hakansson,AlexanderK;Liu,Yang;Davicioni,Elai;Pienta,Kenneth;Nelson,PeterS;Lin,Daniel;Wright,Jona
• 通讯作者: Wright,Jona

Metformin: an antiproliferative agent and methylation regulator in treating prostatic disease?

• DOI: 10.1152/ajprenal.00443.2017
• 发表时间: 2018-03
• 期刊: American journal of physiology. Renal physiology
• 作者: Zongwei Wang;A. Olumi

Obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland.

• DOI: 10.1038/s41391-020-0208-4
• 发表时间: 2020-09
• 期刊: Prostate cancer and prostatic diseases
• 影响因子: 4.8
• 作者: Xue B;Wu S;Sharkey C;Tabatabaei S;Wu CL;Tao Z;Cheng Z;Strand D;Olumi AF;Wang Z
• 通讯作者: Wang Z

Zonal Growth Pattern of the Prostate Is Affected by Age and Body Mass Index.

前列腺的区域生长模式受年龄和体重指数的影响。

• DOI: 10.1097/ju.0000000000002332
• 发表时间: 2022
• 期刊: The Journal of urology
• 作者: Sharkey,Christina;Long,Xingbo;Wang,Zongwei;Al-Faouri,Ra'ad;Gershman,Boris;Tsai,LeoL;Olumi,AriaF
• 通讯作者: Olumi,AriaF