Researchers identify RNA molecule that suppresses prostate tumours

A new study from Washington University School of Medicine in St. Louis, US, has identified an RNA molecule that suppresses prostate tumours and unveiled a potential new drug for future therapies.

“The drugs that we have to treat prostate cancer are effective initially, but most patients start developing resistance, and the drugs usually stop working after a year or two,” explained senior author Professor Nupam Mahajan. “At that point, the options available for these patients are very limited. We are interested in addressing this need and we believe the RNA molecule we have pinpointed may lead to an effective approach.”

Studying the stretch of DNA that codes for the androgen receptor, the researchers discovered that a section of the DNA molecule next to the androgen receptor produced a long noncoding RNA that plays a key role in regulating the androgen receptor and vice versa. Because of its position next to the androgen receptor in the genome, the researchers dubbed it NXTAR (next to androgen receptor).

“In prostate cancer, the androgen receptor is very clever,” continued Mahajan. “Our research shows that it suppresses its own suppressor; essentially, it binds to NXTAR and shuts it down. This means that in all the prostate cancer samples that we study, we rarely find NXTAR, because it is suppressed by the heavy presence of the androgen receptor in these types of tumours.

“We discovered NXTAR by using a drug that my lab developed that suppresses the androgen receptor. When the androgen receptor is suppressed, NXTAR starts to appear. When we saw this, we suspected that we had discovered a tumour suppressor,” Mahajan added.

The drug, called (R)-9b, was developed to knock down expression of the androgen receptor overall, rather than only blocking its ability to bind to testosterone or reducing overall testosterone levels in the body. However in this study, published in the American Association for Cancer Research, (R)-9b served as a tool to reveal the presence and role of NXTAR.

The researchers then showed that restoring NXTAR expression caused the tumours to shrink in mice. Furthermore, they discovered that only one small key section of the NXTAR molecule is sufficient for shutting down the androgen receptor.

“We are hoping to develop both this (R)-9b drug and NXTAR into new therapies for prostate cancer patients who have developed resistance to the front-line treatments,” Mahajan concluded. “One possible strategy is to encapsulate the small molecule drug and the key piece of NXTAR into nanoparticles, perhaps into the same nanoparticle, and shut down the androgen receptor in two different ways.”