New strategy against treatment-resistant prostate cancer identified
RNA molecule suppresses prostate tumor growth

Date:
November 5, 2021
Source:
Washington University School of Medicine
Summary:
A new study has identified an RNA molecule that suppresses prostate
tumors. The scientists found that prostate cancers develop ways to
shut down this RNA molecule to allow themselves to grow. According
to the new research -- conducted in mice implanted with human
prostate tumor samples -- restoring this so-called long noncoding
RNA could be a new strategy to treat prostate cancer that has
developed resistance to hormonal therapies.



FULL STORY ==========================================================================
Many patients with prostate cancer are treated with drugs that lower or
block hormones that fuel tumor growth. While the drugs are effective for
a time, most patients eventually develop resistance to these therapies.


==========================================================================
A new study from Washington University School of Medicine in St. Louis
has identified an RNA molecule that suppresses prostate tumors. The
scientists found that prostate cancers develop ways to shut down this
RNA molecule to allow themselves to grow. According to the new research
-- conducted in mice implanted with human prostate tumor samples --
restoring this so-called long noncoding RNA could be a new strategy to
treat prostate cancer that has developed resistance to hormonal therapies.

The study is published Nov. 5 in Cancer Research, a journal of the
American Association for Cancer Research.

"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 senior author Nupam P. Mahajan, PhD,
a professor of surgery in the Division of Urologic Surgery. "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." The key protein that drives prostate tumor growth, the androgen receptor, binds to testosterone
and stimulates cancer growth. 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 molecule called a
long noncoding RNA. They found that this long noncoding RNA 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," 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 androgen receptor in these types of tumors. 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 tumor suppressor."
The drug, called (R)-9b, was developed to attack a different aspect of
prostate cancer biology, knocking down expression of the androgen receptor overall rather than just blocking its ability to bind to testosterone or reducing overall testosterone levels in the body, as currently approved
drugs do. But in this study, (R)-9b ended up serving as a tool to reveal
the presence and role of NXTAR.

Studying human prostate tumor samples implanted in mice, the researchers
showed that restoring NXTAR expression caused the tumors to shrink. They
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 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 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." Mahajan worked with Washington University's Office of Technology Management to file a patent application
on potential uses of NXTAR as therapeutics. In addition, the Moffitt
Cancer Center in Tampa, Fla., where Mahajan was a faculty member before
joining Washington University, has filed a patent application on the
(R)-9b drug. The (R)-9b inhibitor has been licensed to a biotechnology
startup company called TechnoGenesys. Mahajan and co-author Kiran Mahajan
are co-founders of the company.

This work was supported by the National Cancer Institute (NCI) of the
National Institutes of Health (NIH), grant numbers 1R01CA208258 and 5R01CA227025; the Prostate Cancer Foundation (PCF), grant number 17CHAL06;
and the Department of Defense (DOD), grant number W81XWH-21-1-0202.

The (R)-9b inhibitor has been licensed to a biotechnology startup
company called TechnoGenesys. Mahajan and co-author Kiran Mahajan are co-founders of the company. They also own stock and serve as consultants
to TechnoGenesys.

========================================================================== Story Source: Materials provided by
Washington_University_School_of_Medicine. Original written by Julia
Evangelou Strait. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Ruchi Ghildiyal, Mithila Sawant, Arun Renganathan, Kiran Mahajan,
Eric H
Kim, Jingqin Luo, Ha X Dang, Christopher A Maher, Felix Y Feng,
Nupam P Mahajan. Loss of long non-coding RNA NXTAR in prostate
cancer augments androgen receptor expression and enzalutamide
resistance. Cancer Research, 2021; canres.3845.2020 DOI:
10.1158/0008-5472.CAN-20-3845 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211105134626.htm

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