A team of scientists has found a groundbreaking new way to tackle prostate cancer by reactivating an RNA molecule the cancer has learned to shut down because it impedes its own growth.
The research, published in the journal Cancer Research, offers new hope for patients who have developed a resistance to hormonal therapies, a form of cancer treatment that blocks the body’s ability to produce testosterone and other hormones known to facilitate tumour growth.
“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,” said Nupam P. Mahajan, senior author of the study and a professor of surgery in the Division of Urologic Surgery at the Washington University School of Medicine in St. Louis. “At that point, the options available for these patients are very limited. We are interested in addressing this need — developing new therapies for patients who have developed resistance — and we believe the RNA molecule we’ve pinpointed may lead to an effective approach.”
Prostate cancer is the fourth most common cancer in Canada — and number one among men — with an estimated 23,300 people receiving a diagnosis in 2020, according to the Public Health Agency of Canada. Roughly one in nine Canadian men will be diagnosed with prostate cancer at some point in their lives, with 99 per cent of cases occurring in men over the age of 50. The likelihood of surviving at least five years upon diagnosis is 93 per cent.
The spread of prostate cancer is facilitated by a protein known as the androgen receptor that binds to testosterone, which fuels its growth. Scientists examined the area of DNA that codes this androgen receptor and discovered a section beside it that produces a type of molecule known as a long noncoding RNA. They discovered that this molecule, which they dubbed NXTAR (or next to androgen receptor), plays a key role in regulating the androgen receptor — or would if it weren’t rendered ineffective by the developing cancer.
“In prostate cancer, the androgen receptor is very clever,” Mahajan said. “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.”
The drug, named (R)-9b, was initially designed to stop the expression of the androgen receptor altogether — as opposed to preventing it from binding to testosterone — but instead, it revealed the presence and purpose of NXTAR. After implanting human prostate tumours in mice, the team discovered one key section of the NXTAR molecule, when expressed, shut down the androgen receptor and caused the tumours to shrink.
The discovery opens the door to new therapies for prostate cancer patients whose tumours have become resistant to hormone therapy after months or years of treatment. “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 said.
“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.”
Dave Yasvinski is a writer with Healthing.ca