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.

总结 良性前列腺增生（BPH）和相关的下尿路症状（LUTS）是一个主要的原因 老年男性的发病率，导致直接医疗保健支出和损失的主要经济成本 生产力BPH/LUTS的发病机制是多因素的。然而，目前的医学BPH治疗通常 遵循脚本格式使用两种方法：β-肾上腺素能阻滞剂（β-受体阻滞剂）放松肌肉张力和5 β- 还原酶抑制剂（5ARI）缩小前列腺。许多男性未能通过这些医疗，导致约 在美国每年有12万例外科手术。常见的促炎合并症包括 肥胖和糖尿病。炎症与LUTS严重程度的增加以及治疗失败密切相关。 BPH的现有药物治疗导致进展到手术。自身免疫性疾病 炎症性（AI）疾病和前列腺增生症现在已被确定为常见的合并症，包括银屑病 和类风湿性关节炎。AI疾病患者的BPH患病率增加约50%。我们最近 表明AI疾病治疗，特别是TNF拮抗剂，降低了随后的BPH诊断， 甚至低于基线人群发病率。这种效应在广谱 免疫抑制剂甲氨蝶呤我们还发现， 在用TNF拮抗剂处理的小鼠模型中，存在的增大的腺体的增生和收缩。的 用这些试剂治疗的患者的前列腺显示出减少的增殖和炎症。这强烈 提示靶向免疫调节途径，特别是TNF阻断，可能是有益的， 预防和/或治疗BPH/LUTS。TNF拮抗剂处理的小鼠模型中的通路分析 表明阻断该途径可减少抗原呈递和炎症信号传导 TNF受体2的下游。总体而言，这些变化与TNF阻断剂降低总体 细胞增殖和细胞凋亡的抑制。有有限的医疗选择，以治疗患者 近30年来，BPH/LUTS和没有新的医学治疗方法已经开发出来。这项提案将检验 在随后的组织和基因组分析中进行试点试验的想法，以确定可能同时 有针对性的，并提供数据，以帮助未来的病人分层。这项工作的主要影响将是 测试一种现有的和广泛使用的药物作为治疗BPH的可能的新方法。如果成功，这项工作将 为BPH/LUTS患者人群的新方法与现有疗法的整合奠定了基础， 前列腺肥大我们将追求三个目标，即：1）评价TNF拮抗剂在治疗中的疗效。 BPH/LUTS，2）确定TNF拮抗剂治疗对人前列腺组织的影响，和3）确定 对TNF拮抗剂有不同反应的患者进行分层的遗传预测因子。