1. Gallagher, Amy

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A new study reported by senior author Nupam P. Mahajan, PhD, Professor of Surgery in the Division of Urologic Surgery at Washington University School of Medicine in St. Louis has identified an RNA molecule that suppresses prostate cancer tumor cells.

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"We know the common prostate cancer drugs that have been traditionally prescribed to patients only lower or block the hormones, but does not stop the growth of the cancer cells," he said. "Even the most commonly and presently used drug, enzalutamide, shows that after 1 or 2 years, the cancer cells become resistant to the drug therapy. At that point, the options available for these patients are very limited."


The new therapeutic strategy shows promise for treatment-resistant prostate cancer, which is designed to block a network of signals called the androgen receptor (AR) pathway, to prevent androgens, in particular testosterone, from fueling the growth of prostate tumors.


"Prostate cancer cells can evolve to develop changes wherein the AR avoids the effects of current drug therapies that were designed to block its activity," said Mahajan, who said the new therapy was based on an RNA named NXTAR (next to the AR in the genome). "Given its genomic position and convergent location, we reasoned that NXTAR could influence AR expression or might be affected by it, or possibly both. 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."


The Methodology

With a decade of research to his credit, Mahajan stated the original idea for the current study was focused on identifying the modulation in AR, which binds to testosterone that ultimately activates many other genes responsible for growth of tumor.


"The key protein that drives prostate tumor growth, the AR binds to testosterone and stimulates cancer growth," he said. Studying the stretch of DNA that codes for the AR, his team discovered that a section of the DNA next to the AR produced a molecule called a long-noncoding RNA. They found that this long-noncoding RNA plays a key role in regulating the AR and vice versa.


Mahajan and his team of researchers in his lab found that prostate cancers develop ways to shut down this RNA molecule to allow themselves to grow. "First, we needed to identify the smallest region in the long RNA that we could introduce to the prostate cancer cell to determine if it behaves the same as the RNA in the cancer cell," he said. "We needed to make it very stable because normally the RNA is not stable, and we discovered that it worked nicely in that it could suppress the cancer cell proliferation."


Conducted in mice that were implanted with human prostate tumor samples/cells, Mahajan's current research showed the restoration of the long-noncoding RNA could be a new therapy to treat prostate cancer that has developed a resistance to hormonal therapies.


"We took careful look at levels of this long RNA to notice that most prostate cancers had barely any expression of the NXTAR RNA," he said. "We were surprised to notice another cell line that lacked an AR, had a high expression of NXTAR RNA, which was our first observation only to learn how cleverly the AR works."


Mahajan said that 68 percent of prostate cancer patients exhibited a significant decrease in NXTAR expression in tumors, compared to normal tissues.


"Through some reasoning, we thought about how to introduce NXTAR RNA into the cells to see if it inhibits the growth of the cancer cells," he explained. "Once we had this observation, we did an extensive study to see the effect in different cell lines and also used a mouse model where human prostate cancer cells were introduced with NXTAR and then injected into the mice," said Mahajan. "We found when we introduce NXTAR RNA, prostate tumors significantly lower AR levels and slow down its growth, which proved the point that this long-noncoding RNA behaved as a tumor suppressor."


Potential Future Applications

Now with this phenomenon, his team explored it as a potential therapy for prostate cancer patients.


"In prostate cancer, the androgen receptor is a clever player," said Mahajan, who is also a research member of Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. "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 AR in these types of tumors."


Mahajan and his team discovered that NXTAR starts to appear when the AR is suppressed. "When we saw this, we suspected that we had discovered a tumor suppressor," he said. "It also showed that they didn't need the entire long-noncoding RNA to achieve this effect."


One small, key section of the NXTAR molecule is sufficient for shutting down the AR. "As the first of its kind, the potential therapy derived from this non-coding RNA is named as NXTAR-N5 and has a unique mechanism. It is a small piece of DNA that clamps the AR gene, reducing its levels," said Mahajan, who said that his team discovered NXTAR about 3 years ago, then it took 2 years to complete the work, and another 7 months to publish the research results.


The drug, called (R)-9b, was earlier developed by this team to attack a different aspect of prostate cancer biology, knocking down expression of the AR overall rather than just blocking its ability to bind to testosterone or reducing overall testosterone levels in the body, as currently approved drugs do.


"In this study, (R)-9b ended up serving as an excellent tool to reveal the presence and role of NXTAR," Mahajan said.


The Future With Nanotechnology

"We are hoping to develop both (R)-9b drug and NXTAR-N5 into new therapies for prostate cancer patients who have developed resistance to the frontline treatments," Mahajan noted.


The research team will continue to work on how best to introduce NXTAR-N5 in patients, which he said "will most likely be through nanotechnology. One possible strategy is to encapsulate the small molecule drug and the key piece of NXTAR into nanoparticles, potentially into the same nanoparticle, and shut down the AR in two different ways."


Mahajan said he wants to make this therapy more widely available through pre-IND studies, which will require about 3 years for approval.


Finally, one more hope that he said is based on how the AR works in some women with triple-negative breast cancer (TNBC), Mahajan said his team will explore if the NXTAR-N5 can be used to treat TNBC patients.


"We hope this is a significant advantage to sensitize those tumors of patients who are experiencing drug resistance," he concluded.


Amy Gallagher is a contributing writer.