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Potential new therapeutic targets to treat benign prostatic hyperplasia

Two recent studies explored new potential approaches for treating prostate enlargement. The prostate, a small gland surrounding the urethra just below the bladder, is part of the male reproductive system and commonly becomes enlarged with age. This condition, called benign prostatic hyperplasia (BPH), is caused by the non-cancerous growth of the prostate due to increased reproduction of cells. As the prostate enlarges, it may squeeze the urethra and affect the flow of the urinary stream leading to symptoms involving changes or problems with urination. Many available BPH therapeutics aim to relax the muscles of the bladder and prostate to allow for urine flow.

One study utilized mouse models to explore the impact of targeting a protein called soluble guanylate cyclase, or sGC, on BPH symptoms. This protein is involved in proper functioning (contraction and relaxation) of muscles in the bladder and prostate and affects other processes, such as cell proliferation. Although some approved medicines treat BPH by affecting other proteins in the same pathway, they occasionally lose their effectiveness. In this study, researchers compared urination and prostate characteristics of aged mice displaying BPH-like symptoms with those of younger adult mice. Treatment of aged mice with an sGC-activating compound called cinaciguat for 2 weeks was able to restore normal urinary function in the BPH mice. The researchers also found that cinaciguat was able to reduce the frequency of bladder contractions in a different mouse model of BPH that mimics resistance to some approved therapeutics.

Another study investigated the contribution of autoimmune inflammatory diseases to BPH and the use of autoimmune disease therapeutics to treat the condition. Researchers analyzed the medical records of 112,152 men over the age of 40 and found the prevalence of BPH was substantially higher among individuals with autoimmune diseases compared to those without. However, in further analysis of each BPH diagnosis in relation to the timing of an autoimmune disease diagnosis, the researchers found that BPH was less common in males previously diagnosed with an autoimmune disease compared to those who were not. This result suggested that prior autoimmune disease-specific treatments may effectively treat or reduce the development of BPH. The researchers observed that tissue from donated human BPH prostates contained high levels of an inflammatory molecule, tumor necrosis factor (TNF), and found that TNF exposure triggered certain cells from human prostates to multiply. The researchers therefore investigated whether a class of anti-inflammatory autoimmune disease therapeutics known as TNF antagonists might be effective for treating BPH. Indeed, analyses of prostate tissue donated from people with BPH and of two different BPH mouse models revealed that a TNF antagonist reduced cell multiplication and markers of prostate inflammation compared to untreated controls.

Because TNF antagonist treatment can result in serious side effects, future studies to identify safer alternatives to reduce the inflammatory aspects of BPH will be important. If new treatments, including anti-inflammatory medications or cinaciguat or another sGC activator, are shown to be safe and effective, individuals with BPH may one day have valuable alternatives to existing therapies.

Zabbarova IV, Ikeda Y, Kozlowski MG, …Kanai AJ. Benign prostatic hyperplasia/obstruction ameliorated using a soluble guanylate cyclase activator. J Pathol 256: 442-454, 2022

Vickman RE, Aaron-Brooks L, Zhang R, …Hayward SW. TNF is a potential therapeutic target to suppress prostatic inflammation and hyperplasia in autoimmune disease. Nat Commun 13: 2133, 2022.

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