Effects of TNF Blockade on Human BPH/LUTS

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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.