Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie's Disease Models

This publication in European Urology is a product of the culmination of 7 years of work. The initial idea of taking a phenotypic screening approach rather than a target-based approach has emerged in the early 2010s when it has become apparent that target-based approach to discover and develop new medicines in fibrotic diseases may be futile due to nature of the pathology; the human body's defense mechanisms seem to be always one step ahead of us. When we target a single molecule, another molecule or pathway takes over the lost function of the targeted molecule. And since fibrosis through evolution has so many of these compensatory mechanisms built into its pathophysiology, hitting a single target with a compound and hoping that it will halt the progression of fibrosis or reverse the pathology proved to be the wrong approach. Therefore, we took a different approach called phenotypic screening; an approach proved itself to be more successful than target-based approach when FDA-approved first-in-class drugs are analyzed.¹

In our case, the phenotype we chose was a cell called myofibroblast which is a key cell type in the pathogenesis of Peyronie's disease. During the early stages of Peyronie's disease, most possibly due to repetitive microtrauma and associated inflammatory response, resident fibroblasts are transformed into myofibroblasts. Myofibroblasts have three distinctive features: they proliferate rapidly, they synthesize vast amounts of extracellular matrix proteins such as collagen and they have the ability to contract like smooth muscle cells hence the prefix "myo". Through these functions, myofibroblasts play a central role in the pathophysiology of Peyronie's disease as well as other fibrotic diseases.

Our phenotypic screening, which took 3 years to develop, measures the transformation of resident fibroblasts to myofibroblasts. We isolated fibroblasts from the tunica albuginea of patients who were undergoing surgery for Peyronie's disease. The screening assay has been optimized so that we can now utilize it for medium to high throughput screening. Using this assay, we tested 25 compounds/drugs that have been suggested for the treatment of Peyronie's disease in previous pre-clinical and clinical studies. It should be noted that none of these drugs or compounds have been approved for the treatment of Peyronie's disease. The assay showed that two classes of drugs were successful in inhibiting the transformation of fibroblasts to myofibroblasts: phosphodiesterase type 5 (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil) and selective oestrogen receptor modulators (SERMs; tamoxifen and raloxifene). When any of the drugs from each class are combined, we observed a synergy which has not been reported previously. This synergy between PDE5i and SERMs may be beneficial in halting the progression of fibrosis in men with early-stage Peyronie's disease.

We are aware that earlier clinical studies have conflicting results with these two classes of drugs; however, it should be noted that those clinical studies were conducted in men with late-stage disease. In a limited number of studies with early-stage disease, they actually showed promising results in preventing further progression of the disease. This does make perfect sense if we think how the myofibroblasts work. They proliferate, they excrete collagen and they contract which results in the plaque formation. Once the plaque is formed, it will make no difference to the size of the plaque or the deformity/curvature if the myofibroblasts are inhibited. In other words, what we are proposing is that the combination of PDE5i and SERMs will prevent the formation of new myofibroblasts hence will halt the progression of the disease but will NOT reverse the disease (i.e. will not reverse the plaque/already formed fibrosis). We are hoping to take this combination into a clinical study where we will aim to test it on men with early stages of the disease. We are also investigating how the synergy is occurring at molecular levels between PDE5i and SERMs.

With this opportunity, I would like to thank all my co-authors for their long commitment and dedication to this project as well as all our patients who donated their tissues without which none of this could have been achieved.

Written by: Selim Cellek, MD, Ph.D., FBPhS, Professor of Health and Biomedicine, Director, Medical Technology Research Centre Faculty of Health, Education, Medicine, and Social Care Anglia Ruskin University, Chelmsford, United Kingdom

References:
1. Swinney, (2013) Phenotypic vs. target-based drug discovery for first-in-class medicines. Clinical Pharmacology & Therapeutics, 93 (4), 299–301.

Read the Abstract

Login