Effects of TNF Blockade on Human BPH/LUTS

TNF 阻断对人类 BPH/LUTS 的影响

基本信息

批准号：
10633882
负责人：
Alexander Paul Glaser
金额：
$ 59.1万
依托单位：
NORTHSHORE UNIVERSITY HEALTHSYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10633882
关键词：
Adrenergic Antagonists Affect Aging Antigen Presentation Apoptosis Autoimmune Benign Prostatic Hypertrophy Blood Cell Proliferation Cells Chronic Clinical Collection Data Development Diabetes Mellitus Diagnosis Disease Double-Blind Method Drug usage Effectiveness Environment Failure Flow Cytometry Future Genes Genomics Gland Health Expenditures Human Humira Immune Immunohistochemistry Incidence Inflammation Inflammatory Link Measures Medical Methotrexate Morbidity - disease rate Muscle Tonus Muscle relaxation phase Obesity Operative Surgical Procedures Oxidoreductase Pathogenesis Pathway Analysis Pathway interactions Patient Outcomes Assessments Patients Placebos Population Predisposition Prevalence Prevention Procedures Productivity Proliferating Prophylactic treatment Prostate Prostatic Prostatic hypertrophy Psoriatic Arthritis Randomized Rheumatoid Arthritis Schedule Severities Signal Transduction Symptoms TNF gene Testing Therapeutic Time Tissues Treatment outcome Tumor Necrosis Factor Receptor United States Work adalimumab antagonist arm comorbidity derepression economic cost efficacy evaluation efficacy testing genetic predictors genetic risk factor genetic variant immunoregulation improved individual response inhibitor intravesical lower urinary tract symptoms men mouse model novel strategies patient population patient stratification pilot trial randomized placebo controlled trial response single-cell RNA sequencing transcriptome sequencing

项目摘要

SUMMARY Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are a major cause of morbidity in aging men, resulting in major economic costs in both direct healthcare expenditure as well as lost productivity. The pathogenesis of BPH/LUTS is multifactorial. However, current medical BPH treatment generally follows a scripted format using two approaches: -adrenergic blockers (-blockers) to relax muscle tone and 5- reductase inhibitors (5ARI) to shrink the prostate. Many men fail these medical treatments, resulting in around 120,000 surgical interventions annually in the United States. Common pro-inflammatory co-morbidities include obesity and diabetes. Inflammation is strongly associated with increased LUTS severity and also with the failure of existing medical treatments for BPH resulting in progression to surgery. Links between autoimmune inflammatory (AI) diseases and BPH are now well established with common comorbidities including psoriasis and rheumatoid arthritis. AI disease patients have around a 50% increase in BPH prevalence. We recently showed that AI disease treatment, specifically with TNF-antagonists, reduced subsequent BPH diagnoses down to or even below the baseline population incidence. This effect was not observed with the broad spectrum immune-suppressant methotrexate. We also showed both suppression of the development of prostate hyperplasia and the shrinkage of existing enlarged glands in mouse models treated with TNF-antagonists. The prostates of patients treated with these agents demonstrate reduced proliferation and inflammation. This strongly suggests that approaches that target immunomodulatory pathways, specifically TNF blockade, may be beneficial in the prevention and/or treatment of BPH/LUTS. Pathway analysis in TNF-antagonist-treated mouse models demonstrated that blockade of this pathway reduces antigen presentation and inflammatory signaling downstream of TNF receptor 2. Overall these changes were consistent with TNF blockade reducing both overall cellular proliferation and the suppression of apoptosis. There are limited medical options to treat patients with BPH/LUTS and no new medical treatments have been developed in nearly 30 years. This proposal will test that idea in a pilot trial with subsequent tissue and genomic analysis to identify pathways that may be concurrently targeted as well as provide data to assist in future patient stratification. The major impact of this work will be to test an existing and widely used drug as a possible novel approach to treat BPH. If successful, this work would set the stage for integrating a new approach with existing therapies for the BPH/LUTS patient population with large prostates. We will pursue three aims, that will: 1) Evaluate the efficacy of TNF antagonist action in BPH/LUTS, 2) Define the consequences of TNF antagonist therapy on human prostate tissue, and, 3) Identify genetic predictors to stratify patients with differential response to TNF antagonists.

概括良性前列腺增生 (BPH) 和相关的下尿路症状 (LUTS) 是一个主要原因老年男性的发病率，导致直接医疗支出和损失的重大经济成本 BPH/LUTS 的发病机制是多因素的，但目前的 BPH 治疗方法普遍如此。遵循脚本格式，使用两种方法：放松肌肉张力的 α-肾上腺素能阻滞剂（α-阻滞剂）和 5α- 还原酶抑制剂（5ARI）可缩小前列腺，许多男性无法通过这些药物治疗，导致周围的疾病。美国每年进行 120,000 例手术干预，其中包括常见的促炎症并发症。肥胖和糖尿病与 LUTS 严重程度以及失败密切相关。现有的 BPH 治疗方法导致进展为手术之间的联系。炎症 (AI) 疾病和 BPH 现已明确，常见合并症包括牛皮癣最近，类风湿性关节炎患者的 BPH 患病率增加了约 50%。表明 AI 疾病治疗，特别是使用 TNF 拮抗剂，可以减少随后的 BPH 诊断达到或什至低于基线人群发病率，在广谱范围内未观察到这种效应。我们还显示了免疫抑制剂甲氨蝶呤对前列腺发育的抑制作用。在用 TNF 拮抗剂治疗的小鼠模型中，存在增生和现有肿大腺体的收缩。用这些药物治疗的患者的前列腺增殖和炎症减少。表明针对免疫调节途径（特别是 TNF 阻断）的方法可能是有益的在 TNF 拮抗剂治疗的小鼠模型中预防和/或治疗 BPH/LUTS。证明阻断该途径可减少抗原呈递和炎症信号传导 TNF 受体 2 下游。总体而言，这些变化与 TNF 阻断减少总体一致细胞增殖和细胞凋亡的抑制治疗患有此病的患者的医疗选择有限。近 30 年来没有开发出 BPH/LUTS 的新疗法。该提案将检验这一点。在试点试验中提出想法，并进行随后的组织和基因组分析，以确定可能同时存在的途径这项工作的主要影响将是有针对性的并提供数据以协助未来的患者分层。测试一种现有且广泛使用的药物作为治疗 BPH 的可能新方法。如果成功，这项工作将成为可能。为将新方法与针对 BPH/LUTS 患者群体的现有疗法相结合奠定了基础我们将追求三个目标，即： 1) 评估 TNF 拮抗剂作用的功效。 BPH/LUTS，2) 定义 TNF 拮抗剂治疗对人类前列腺组织的影响，以及，3) 识别遗传预测因子对 TNF 拮抗剂有不同反应的患者进行分层。