ROR-γ Antagonists May Help Combat Castration-Resistant Prostate Cancer

Investigators are now reporting that it may be possible to strategically target the overexpression of the androgen receptor (AR) gene and its protein, and prevent castration-resistant prostate cancer (CRPC) in a new way. A study published in Nature Medicine reports that suppressing the nuclear receptor protein ROR-γ with small-molecule compounds may reduce AR levels in CRPC and stop tumor growth.  

“This is a new target and a totally new way of hitting prostate cancer,” said lead study author Hongwu Chen, PhD, professor in the Department of Biochemistry and Molecular Medicine at the University of California Davis, in a news release.

In the vast majority of prostate cancers, antiandrogen therapies are highly effective; however, in many cases, resistance develops. Chen et al. report that suppressing retinoic acid receptor–related orphan receptor γ (ROR-γ) circumvents resistance. Because the ROR-γ protein is required for AR gene expression, ROR-γ inhibition strongly reduces AR protein levels in tumor cells.

Study co-author Christopher Evans, MD, who is professor and chairman of the Department of Urology at UC Davis, said as patients become resistant to existing agents, the AR becomes mutated, amplified, and spliced. The ROR-γ suppression mechanism blocks the actual expression of the AR and its spliced forms, according to Dr. Evans.

This study showed that ROR-γ is overexpressed and amplified in metastatic CRPC tumors and drives AR expression in these tumors.

Researchers studied a number of small molecule ROR-γ antagonists, both in cell lines and human tumors in mice. In each model, suppressing ROR-γ reduced AR gene expression and AR protein levels, blocking tumor growth. These inhibitors showed broad effectiveness, inhibiting several AR variants, including AR-V7, which has been linked to resistance to advanced prostate cancer therapies enzalutamide (Xtandi) and abiraterone (Zytiga). The investigators found that ROR-γ antagonists suppressed tumor growth in multiple AR-expressing xenograft prostate cancer models.  The researchers were able to effectively sensitized CRPC tumors to enzalutamide without overt toxicity in mice.

The researchers believe these new findings help establish ROR-γ as a key player in CRPC by acting upstream of AR. These findings come at a fortuitous time. Currently, there are a number of ROR-γ antagonists in the pipeline. They are being investigated for treating rheumatoid arthritis (RA), inflammatory bowel disease, psoriasis, and other autoimmune conditions. Dr. Chen said some of these experimental agents are orally available and have been found to be safe in early clinical trials. Now, it is hoped that these agents can be used to combat advanced prostate cancer along with autoimmune diseases.