New Therapeutic Target for Prostate Cancer

Researchers at the University of California, Davis, School of Medicine in Sacramento have found a potential therapeutic target for castration-resistant prostate cancer (CRPC): a nuclear receptor called RORγ. According to a new study, RORγ regulates the androgen receptor (AR), which is frequently overexpressed and hyperactivated in CRPC. AR is a key therapeutic focus, with the antiandrogens enzalutamide (Xtandi; Astellas) and abiraterone acetate (Zytiga; Janssen) having been approved in the last few years.

“We decided to look at factors other than AR that might play a role in prostate cancer progression,” says the study's senior author Hong-Wu Chen, PhD. Because RORγ influences the production of proinflammatory helper T cells, it's been extensively studied as a target for autoimmune diseases such as rheumatoid arthritis and psoriasis. However, little is known about this protein in cancer, so when Chen and his colleagues examined prostate tumor gene expression data and observed high levels of RORγ and its gene, RORC, in metastatic CRPC samples, their interest was piqued.

The researchers set out to investigate the relationship between RORγ and AR by knocking down RORC in CRPC cell lines or inhibiting RORγ with small-molecule antagonists currently in development. Both methods suppressed AR and several variants—including AR-V7, which has been linked to enzalutamide resistance—and markedly inhibited the proliferation of these cells.

Mechanistically, Chen and his group discovered that RORγ binds to a specific region of AR and stimulates the latter's transcription, aided by RORγ's recruitment of SRC1 and SRC3. When this binding region was deleted, the abundance of AR transcripts dropped considerably.

The team then treated mice bearing human prostate tumors, including an enzalutamide-resistant model, with the same RORγ antagonists used in CRPC cell lines. Tumor growth was impeded in these mice, with no significant toxicities. Likely because of low to undetectable RORγ levels in normal tissue, the antagonist effects were tumor-specific—an advantage over antiandrogen therapy, which also suppresses the growth and function of normal androgen-responsive tissues, Chen points out.

Other regulators of AR expression include the transcription factors E2F1 and TCF, and the histone demethylase LSD1. However, RORγ is “one of the first, besides AR itself, that's readily druggable,” Chen says—most of the other molecular players lack inhibitors or are trickier to target therapeutically. RORγ antagonists, by suppressing AR at the transcriptional level, could “mitigate or even eliminate the root cause of CRPC,” namely, an overabundance of AR signaling.

“AR signaling mechanisms are incompletely understood, so identifying new regulators is important,” says William Hahn, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA. He notes that RORγ antagonists, while intriguing, “seem to induce tumor stasis rather than regression,” and “whether they'll be useful in the presence of what's now a number of AR-directed therapies” for CRPC is an open question.

That RORγ inhibition appears effective in enzalutamide-resistant CRPC may pave the way for new treatment options, says Roland Schüle, PhD, of the University of Freiburg in Germany. For instance, RORγ antagonists combined with AR-targeting drugs, or iterative cycles of each, could slow the resistance that almost always develops against antiandrogen therapy.

“The [CRPC] field is moving fast, but still intensely focused on AR,” Chen observes. “We think including more molecular targets in the therapeutic scope is a strategy worth considering.” –Alissa Poh