Histone Deacetylase Inhibitors as Therapeutics for Endometriosis

Xin Li; Xishi Liu; Sun-Wei Guo

Disclosures

Expert Rev of Obstet Gynecol. 2012;7(5):451-466. 

In This Article

Abstract and Introduction

Abstract

Endometriosis is a common gynecological disorder affecting mostly women of reproductive age. Its presenting symptoms include dysmenorrhea, chronic pelvic pain and infertility. There is a pressing need to develop more efficacious therapeutics, preferably with improved safety and cost profiles. Unfortunately, thus far the drug development progress has been frustratingly slow. In this article, published data in support of the notion that endometriosis is an epigenetic disease are reviewed. The desirable properties of histone deacetylase inhibitors as therapeutics for treating endometriosis are enumerated, and the obstacles in evaluating histone deacetylases in clinical trials are listed. It is argued that, from the drug discovery standpoint, repurposing of valproic acid is justifiable. Finally, the areas in need of further research are exposed.

Introduction

Characterized by the growth of endometrial-like glands and stroma outside of the uterine cavity, endometriosis is a common gynecological condition with a puzzling pathogenesis.[1] It is responsible for dysmenorrhea, pelvic pain and subfertility, and is a leading cause of disability in women of reproductive age,[2] impacting negatively on patients' physical, mental, relational and social well-being.[3] It also consumes a tremendous amount of healthcare resources. In the USA, endometriosis is the third leading cause of gynecologic hospitalization.[3,4] In China, endometriosis-related surgeries constitute about one quarter of all gynecological surgeries.

Even though laparoscopy is the definitive treatment for endometriosis, medical treatment is often needed for first- and second-line therapy. Currently, all medical treatment modalities for endometriosis have a limited efficacy in relieving endometriosis-associated pain, often with relatively short-term effect.[5] In addition, they have undesirable, and sometimes severe, side effects,[6–9] prohibiting the long-term management that may be needed for endometriosis. The continuous use of combined oral contraceptives, while it appears to be cost effective in treating endometriosis, is still far from ideal. Accordingly, there is a clear need for more efficacious therapeutics, preferably with improved safety and cost profiles.[10,11]

However, the road to endometriosis drug research and development (R&D) is tortuous. A survey conducted 3 years ago found that 57 endometriosis-related clinical trials were registered[12] and 25 of them were listed as completed and two as suspended. In all, there were 15 completed Phase II/III trials on the efficacy of various promising compounds. However, only three of these trials (20%) had published their results.[12]

Three years have since passed, and the number of registered trials now swells to 140.[201] However, a cursory overview found that, regrettably, little has changed. Given the enormous cost of conducting clinical trials and the fact that the very purpose of registration is later publication, failure to publish the trial results may signal the efficacy problem, safety problem or both. It is not surprising that there is a palpable disappointment over the R&D in endometriosis: Vercellini et al. recently likened the process to 'waiting for Godot'.[13]

In this article, the published data in support of the notion that endometriosis is an epigenetic disease are reviewed. The desirable properties of histone deacetylase inhibitors (HDACIs) as therapeutics for treating endometriosis are enumerated and the obstacles in testing histone deacetylases (HDACs) in clinical trials are listed, and, finally, areas in need of further research are exposed.

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