Researchers at Vanderbilt University Medical Center have “turned back the clock” in a mouse model of metaplasia — precancerous stomach lesions — raising hopes that gastric cancer, a worldwide scourge that’s rising in the United States, can be prevented.
“This was totally unexpected,” said James Goldenring, M.D., Ph.D., the Paul W. Sanger Professor of Experimental Surgery and Co-Director of the Epithelial Biology Center. “I would never have believed it a year and a half ago.”
The “clock” is abnormal activation of Ras, a signaling protein that regulates cell growth and survival. Ras mutations are found in up to one-third of all human cancers. Ras activation, possibly triggered by other signaling molecules, recently was identified in a large percentage of gastric cancers.
Goldenring and Steven Leach, M.D., a former Vanderbilt faculty member now at the Memorial Sloan Kettering Cancer Center in New York, found that Ras activation in gastric chief cells, which secrete digestive enzymes, was involved in the “full spectrum” of transitions leading to precancerous metaplasia in mice.
The surprise came when the animals were given selumetinib, a drug now in clinical trials that blocks MEK, an enzyme downstream of Ras activation. Not only was metaplasia halted, but normal stomach cells repopulated the stomach, turning it “back to normal,” they reported recently in the journal Gastroenterology.
Eunyoung Choi, Ph.D., research instructor in Surgery at Vanderbilt, was the paper’s first author.
It appears that underneath all the abnormal metaplastic cells hides a lineage of normal progenitor cells which can regenerate the normal mucosal layer of the stomach, Goldenring said. When Ras activation was blocked, the normal cells actually pushed the abnormal tissue right out of the mucosa, he said.
The researchers are extending their studies in gerbils, another animal model, and with colleagues at Yonsei University in Seoul, South Korea, they are preparing to test MEK inhibition in patients who have had local endoscopic removal of a stage 1 gastric cancer.
Koreans have one of the highest incidences of gastric cancer in the world. Most cases of gastric cancer are triggered by Helicobacter pylori, a bacterium that infects the stomach lining.
But other factors must play a role, Goldenring said.
Metaplasia persists, despite antibiotic treatment to clear the infection. Even after endoscopic resection to remove early gastric cancer, patients still have a 2 to 5 percent annual risk of a second cancer occurring elsewhere in the stomach.
If short-term treatment with selumetinib is successful in reversing metaplasia in patients in Korea, it could be tried as a form of chemoprevention for patients with metaplasia in other countries in Asia and South America that have high gastric cancer rates.
“It makes a lot more sense to me to treat a precancerous lesion than to try to treat a big cancer,” Goldenring said.
The research was supported by the U.S. Department of Veterans Affairs, the National Institutes of Health, and the T.J. Martell Foundation.
