Small molecule may prevent metastasis in colorectal cancer

Date:
October 6, 2021
Source:
Rockefeller University
Summary:
The compound works by hindering a key pathway that cancer cells rely
upon to hoard energy, and is already undergoing clinical trials.



FULL STORY ========================================================================== Colorectal cancer is projected to claim 53,000 lives in the United States
this year alone and, as with most cancers, the disease is deadliest
when it metastasizes. It follows that the most effective way to control
it would be a drug that targets metastasis itself -- preventing cancer
cells from breaking off the primary tumor, or reining in rogue cells
before they spread throughout the body and seed secondary tumors.


==========================================================================
Now, a new study identifies a small molecule that could, in the
future, be administered alongside standard chemotherapies to stave
off colorectal cancer metastasis. The research, published in Science
Advances, demonstrated how the compound, named RGX-202, foils a key
pathway that cancer cells rely upon to hoard energy, thereby killing
them and shrinking tumors in mice.

The findings have already led to a clinical trial in humans and may
eventually give rise to a novel therapy that increases survival rates
for multiple gastrointestinal cancers.

"Colorectal cancer is one of the top causes of cancer-related mortality,"
says Rockefeller's Sohail Tavazoie, head of the Elizabeth and Vincent
Meyer Laboratory of Systems Cancer Biology. "We've found a critical
pathway that promotes colorectal cancer metastasis and a novel therapeutic
that appears to inhibit it." Stockpiling phosphocreatine Back in 2016, researchers in the Tavazoie lab noticed that colorectal cancer cells
had developed an ingenious strategy for surviving under oxygen-poor
conditions. The tumors were mass-producing a unique enzyme within their
cells, only to pump the enzyme out into the extracellular space. There,
the enzyme would convert the metabolite creatine (which is abundant
outside of cells) into phosphocreatine, which the cancer cells would
finally import back across their membranes.



==========================================================================
The cancer cells were manufacturing and stockpiling phosphocreatine.

That was interesting to Tavazoie, because phosphocreatine is just what
a tumor needs to survive and thrive. Phosphocreatine is energy-rich --
stored in healthy muscle to ensure that there's always enough spare
energy for key metabolic events to go off without a hitch -- and it is
one of the few compounds that cells can use to produce energy in the
absence of oxygen. For notoriously hypoxic gastrointestinal cancers, phosphocreatine is a must-have.

Upon further investigation, Tavazoie and colleagues ultimately discovered
the lynchpin of the entire energy-hoarding process: SLC6A8, a channel
embedded in the cell membrane that functions as a gateway for incoming phosphocreatine and creatine.

"We hypothesized that, if we inhibited this channel, metastasis rates
would decrease because the cancer cells would be unable to bring in the phosphocreatine," Tavazoie, the Leon Hess Professor, says.

Several laboratories subsequently ran with Tavazoie's theory. And indeed, follow-up studies confirmed that this pathway, built around a single
transport channel, was likely influencing the growth and metastasis of
many cancer types, from breast cancer to pancreatic cancer.



==========================================================================
A molecular monkey wrench Tavazoie and colleagues chose to continue
focusing on colorectal cancer and began searching for molecules that bore enough resemblance to phosphocreatine to gum up the channel by tricking
it into binding an imposter. His team, led by Isabel Kurth, Norihiro
Yamaguchi, Celia Andreu-agullo and Masoud Tavazoie, landed on the small molecule RGX-202, which their coauthors at the biopharmaceutical company Inspirna further developed into a potent oral drug candidate. (Sohail
Tavazoie is a scientific cofounder of Inspirna).

RGX-202, their work revealed, reduced colorectal cancer tumor growth
across the board in mice, impacting even tumors with mutations that
are currently considered undruggable with targeted therapies. In mouse
models, the small molecule also prevented metastasis to the liver and functioned well alongside frontline chemotherapies, working in concert
with existing drugs to beat back tumors.

Encouraged by these results, scientists and clinicians at multiple institutions, along with Inspirna researchers, began a Phase 1 trial in
humans with advanced stage colorectal cancer.

"The trial demonstrated that the compound is safe and alters creatine metabolism in humans, just as it did in mice," Tavazoie says. "We also
observed improvements in patient outcomes, suggesting that the compound
should be investigated in further clinical trials." Toward a first-line therapeutic One pressing question, which future studies will address,
is how exactly RGX- 202 inhibits the channel. "A simple notion would be
that it gets into the transport channel and plugs it up, but we do not
yet know, mechanistically, how that works," Tavazoie says. "All we know
is that, when we introduce this small molecule that looks like creatine,
the channel becomes impaired." In the meantime, Tavazoie and colleagues
intend to move their research into a Phase 2 trial as early as 2022,
during which metastatic colorectal cancer patients whose cancers have progressed on frontline chemotherapy will receive RGX-202 alongside conventional chemotherapy. Eventually the researchers hope the therapy
will also prove able to prevent metastasis from occurring the in first
place.

"Our ultimate goal is to prevent, not just treat, relapse," Tavazoie says.

========================================================================== Story Source: Materials provided by Rockefeller_University. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Isabel Kurth et al. Therapeutic targeting of SLC6A8 creatine
transporter
suppresses colon cancer progression and modulates human creatine
levels.

Science Advances, 2021 DOI: 10.1126/sciadv.abi7511 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/10/211006160055.htm

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