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.

摘要 良性前列腺增生症(BPH)和相关的下尿路症状(LUTS)是主要原因 老年男性发病率的增加，导致直接医疗支出的重大经济成本以及损失 生产力。BPH/LUTS的发病机制是多因素的。然而，目前医学上治疗前列腺增生症的方法一般 遵循脚本格式，使用两种方法：肾上腺素能阻滞剂(阻滞剂)放松肌肉张力和5- 还原酶抑制剂(5ARI)，以缩小前列腺。许多男性在这些治疗中失败了，导致了 在美国，每年有12万例外科手术。常见的促炎共病包括 肥胖和糖尿病。炎症与LUTS严重程度的增加和衰竭密切相关 现有的治疗良性前列腺增生症的药物导致了手术的进展。自身免疫之间的联系 炎症性疾病(AI)和良性前列腺增生症(BPH)现在与包括牛皮癣在内的常见并存疾病有很好的关系 和类风湿性关节炎。AI疾病患者的BPH患病率增加了约50%。我们最近 显示人工智能疾病的治疗，特别是使用肿瘤坏死因子拮抗剂，减少了随后的BPH诊断 达到或甚至低于基线人口发病率。这一效应在广谱范围内没有观察到。 免疫抑制药甲氨蝶呤。我们还显示了对前列腺发育的抑制 用肿瘤坏死因子拮抗剂治疗的小鼠模型中现存增大的腺体的增生和收缩。这个 接受这些药物治疗的患者的前列腺表现出减少的增殖和炎症。这一点很强烈 提示针对免疫调节途径的方法，特别是肿瘤坏死因子阻断，可能是有益的。 在预防和/或治疗BPH/LUTS方面。肿瘤坏死因子拮抗剂治疗小鼠模型的通路分析 证明阻断这一途径可以减少抗原提呈和炎症信号。 肿瘤坏死因子受体2下游。总体而言，这些变化与肿瘤坏死因子阻断一致，总体上降低了 细胞增殖和细胞凋亡的抑制。有有限的医疗选择来治疗患者 BPH/LUTS，近30年来一直没有新的治疗方法。这项提案将检验这一点 通过后续的组织和基因组分析来确定可能同时存在的途径的试点试验中的想法 有针对性的，并提供数据，以帮助未来的患者分层。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，作为一种可能的治疗BPH的新方法。如果成功，这项工作将 为BPH/LUTS患者群体的新方法与现有疗法的整合奠定了基础 大的前列腺。我们将追求三个目标，即：1)评估肿瘤坏死因子拮抗剂作用在 BPH/LUTS，2)定义肿瘤坏死因子拮抗剂治疗对人前列腺组织的影响，以及，3)确定 对对肿瘤坏死因子拮抗剂有不同反应的患者进行分层的遗传预测因子。