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New Research Identify A Way To Delay Colorectal Metastasis

Researchers have identified a small molecule that can be administered alongside standard chemotherapies to prevent or delay colorectal metastasis.
The research, published in Science Advances, mentions how the compound, RGX-202, obstructs a vital pathway that the cancer cells depend on to hoard energy, thus killing them and diminishing the tumors during a test conducted on mice. The study is supposed to lead to a novel therapy that increases survival rates for multiple gastrointestinal cancers.

Sohail Tavazoie, head of the Elizabeth and Vincent Meyer Laboratory of Systems Cancer Biology, Rockefeller University said, "Colorectal cancer is one of the top causes of cancer-related mortality. We've found a critical pathway that promotes colorectal cancer metastasis and a novel therapeutic that appears to inhibit it."

Researchers in the Tavazoie lab had in 2016 found that colorectal cancer cells can survive in oxygen deficiency by making the tumor produce a unique enzyme inside their cells, in large quantities which were later pumped out into the extracellular space. There this enzyme would convert the metabolite creatine into phosphocreatine, which the cancer cells would spread across their membranes.

In a nutshell, the cancer cells had evolved to manufacture and stockpile phosphocreatine. The researchers were fascinated because phosphocreatine is a must-have for notoriously hypoxic gastrointestinal cancers as it endured that energy is stored in healthy muscles important metabolic events to go on without any hindrance. And being one of the few compounds that cells can use to produce energy in the absence of oxygen, it is just what a tumor needs to survive and thrive.

Upon further investigation, Tavazoie and fellow researchers concluded SLC6A8, a channel embedded in the cell membrane that functions as a gateway for incoming phosphocreatine and creatine, as the keystone of the entire energy hoarding process.

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

Tavazoie and colleagues focused on colorectal cancer and continued to look for molecules that bore enough resemblance to phosphocreatine to gum up the channel by tricking it into the binding as an impostor.

Under the guidance of Isabel Kurth, Norihiro Yamaguchi, Celia Andreu-agullo, and Masoud Tavazoie, his team found RGX-202. Biopharmaceutical company Inspirna has developed the molecule into a potent oral drug candidate.

RGX-202 has significantly increased the blockade of colorectal cancer tumor growth in mice, by attacking the tumors that were undruggable by the existing therapies. In mouse models, the small molecule also prevented metastasis to the liver and functioned at par with frontline chemotherapies.

The success in these experiments led the scientists and clinicians at multiple institutions, along with Inspirna researchers, to begin 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. We also observed improvements in patient outcomes, suggesting that the compound should be investigated in further clinical trials," he added.

However, the researchers are yet to put their fingers on how exactly RGX-202 obstructs 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," according to Tavazoie. "All we know is that when we introduce this small molecule that looks like creatine, the channel becomes impaired."

The research is expected to move into a Phase 2 trial as early as 2022 with patients whose cancers have progressed on frontline chemotherapy will be treated with RGX-202 alongside conventional chemotherapy. The researchers are focusing on the prevention of cancer, rather than treatment.

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

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