Effects of TNF Blockade on Human BPH/LUTS

TNF 阻断对人类 BPH/LUTS 的影响

• 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
• 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

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）是主要原因 老化男性的发病率，导致直接医疗支出和损失的主要经济成本 生产率。 BPH/LUTS的发病机理是多因素的。但是，当前的医疗BPH治疗 使用两种方法遵循脚本格式：-肾上腺素阻滞剂（阻滞剂）放松肌肉张力和5-- 减少抑制剂（5ARI）以收缩前列腺。许多男人失败了这些药物，导致 每年在美国进行12万手术干预措施。常见的促疾病合并症包括 肥胖和糖尿病。炎症与LUTS严重程度的增加密切相关，也与失败有关 现有的BPH药物治疗导致手术进展。自动免疫之间的链接 炎症（AI）疾病和BPH现在已经建立了众所周知的牛皮癣（包括牛皮癣） 和类风湿关节炎。 AI病患者的BPH患病率增加了约50％。我们最近 表明AI疾病治疗，特别是与TNF抗逆邦波大战的治疗，随后的BPH诊断降低了 到基线人口事件或以下。在广泛的光谱中未观察到这种效果 免疫抑制方法二氧我们还显示了对前列腺发展的抑制 在用TNF抗抗氮剂处理的小鼠模型中，增生和现有肿大的腺体收缩。 用这些药物治疗的患者的前列腺表明增殖和炎症减少。这很强烈 提出针对免疫调节途径，特别是TNF封锁的方法可能是有益的 在预防和/或BPH/LUTS的治疗中。 TNF-Antagonist处理的小鼠模型中的途径分析 证明该途径的阻塞减少了抗原表现和炎症信号传导 TNF受体2的下游。总的来说，这些变化与TNF封锁一致 细胞增殖和凋亡的抑制。治疗患者的医疗选择有限 在将近30年的时间里，BPH/LUTS和未开发新的医疗治疗。该建议将测试 在一项试验试验中进行的想法，随后进行组织和基因组分析，以鉴定可能同时同时进行的途径 针对和提供数据以帮助未来的患者分层。这项工作的主要影响是 测试现有且广泛使用的药物作为治疗BPH的新方法。如果成功，这项工作将 为将新方法与BPH/LUTS患者人群的现有疗法相结合的阶段 大前列物。我们将追求三个目标，这将：1）评估TNF拮抗剂行动的效率 BPH/LUTS，2）定义TNF拮抗剂治疗对人前列腺组织的后果，3）确定 遗传预测因素以分层对TNF拮抗剂反应差异的患者。