HONG KONG — The findings of a new study of gene regulation by androgen receptor (AR) splice variants (AR-Vs) by U.S and Chinese scientists could provide a pivotal pathway for drug designers to target, in order to disrupt AR-V signaling as a novel strategy for the effective treatment of advanced prostate cancer.

According to the U.S. Centers for Disease Control and Prevention, prostate cancer is the most common cause of cancer in American men and, after lung cancer, the second leading cause of cancer-related death, with most prostate cancer-related deaths being due to advanced metastatic disease.

While the majority of prostate cancers are initially androgen-dependent and respond to androgen ablation therapy with castration or with antihormone treatments, most such cancers will eventually relapse and progress into incurable castration-resistant hormone-refractory prostate cancer.

The underlying mechanisms of prostate cancer have therefore long been the focus of intensive investigation for the development of more effective treatments.

There is now an increasing amount of clinical and basic research evidence that the activity of the AR remains a prerequisite for the development of castration-resistant prostate cancer.

Multiple mechanisms exist whereby the AR is re-activated under androgen-depleted conditions, which may be involved in the development of castration resistance, with the relatively recent identification of AR-Vs contributing further to that complexity.

Active AR-Vs lacking the ligand-binding domain have not only been implicated in the pathogenesis of castration-resistant prostate cancer, but also in mediating resistance to newer drugs that target the androgen axis, such as Xtandi (enzalutamide, Medivation Inc. and Astellas Pharma Inc.).

A synthetic nonsteroidal anti-androgen, which elicits marked reductions in levels of prostate-specific antigen (PSA), Xtandi was approved for the treatment of castration-resistant cancer by the FDA in August 2012. Promising phase II results were also reported with the anti-androgen therapy in AR-positive triple-negative breast cancer at the 2015 annual meeting of the American Society of Clinical Oncology in Chicago. (See BioWorld Today, June 10, 2015).

Although anti-androgens such as Xtandi represent a breakthrough in the treatment of castration-resistant prostate cancer, approximately 20 percent to 40 percent of patients have primary resistance and fail to respond in terms of reduced PSA levels, while virtually all patients who initially respond to Xtandi eventually acquire secondary resistance.

AR-Vs are known to regulate the expression of both canonical and full-length AR gene targets, and of a unique set of cancer-specific gene targets, many of which are involved in regulation of the cell cycle. However, little has been known about the mechanism by which AR-Vs control AR gene expression.

However, the new study by researchers at Tulane University School of Medicine in New Orleans has now clarified the mechanism underlying the mediation of AR gene regulation by AR-Vs, they reported in the Aug. 18, 2015, online first issue of Cancer Research.

They discovered that two major AR-Vs not only combine with each other, but also combine with full-length AR in an androgen-independent manner, a process known as heterodimerization.

"Our study is the first to show the dimeric nature of AR-Vs in live cells and represents a key step in delineating the mechanism by which AR-Vs mediate gene regulation," said lead researcher Yan Dong, an associate professor in the Department of Structural and Cellular Biology, Tulane University School of Medicine, Tulane Cancer Center.

"In addition, the heterodimerization of the two major AR-Vs with the full length AR gene leads to its androgen-independent activation, contributing to castration resistance," said Yang, who was formerly a professor in the College of Life Sciences at Jilin University in China, which contributed to the Tulane study.

Using assay techniques such as bimolecular fluorescence complementation and bioluminescence resonance energy transfer, "We found that heterodimerization of AR-V and full length AR- was mediated by N- and C-terminal interactions and by the DNA-binding domain of each molecule, whereas AR-V homodimerization was mediated only by DNA-binding domain interactions," said Dong.

"Notably, dimerization of AR-V was necessary to transactivate target genes and to confer castration-resistant cell growth. This finding indicates that disrupting AR-V dimerization may represent an effective means to suppress AR-V signaling and thereby castration resistance," she told BioWorld Today.

"Our results clarify the mechanism by which AR-Vs mediate gene regulation and provide a pivotal pathway for rational drug design to disrupt AR-V signaling as a rational strategy for the effective treatment of advanced prostate cancer," said Dong.

Regarding the implications of her group's research for the development of new treatments for advanced prostate cancer, "Drugs should be developed that can disrupt AR-V dimerization," said Dong, adding "We are currently screening for compounds that can inhibit AR-V activity."