Researchers at Vanderbilt University Medical Center have created the world’s first laboratory model of precancerous changes in the lining of the stomach, a scientific tour de force that is helping to unlock the mysteries of gastric cancer development.
Their achievement, described recently in the journal Nature Communications, is aiding the search for potential new drugs that could slow — and perhaps even reverse — precancerous changes in the stomach in humans.
This is especially important for patients in Asia, Russia and South America, where the incidence of gastric cancer is significantly higher than in other parts of the world. Gastric cancer is the third leading cause of cancer deaths worldwide after lung and colorectal malignancies.
Until now it has been difficult to identify which cells are involved in the steps leading to gastric cancer, notably the development of precancerous stomach lesions called metaplasia, and later, dysplasia, the appearance of abnormal cells.
Using their model, the VUMC scientists identified a new population of stem cells that arise during dysplasia. “We think this is the critical transition point between pre-cancer and cancer,” said the paper’s senior author, Eunyoung Choi, PhD, assistant professor of Surgery.
Previously Choi and colleagues showed that a MEK inhibitor, a drug which blocks the Kras signaling pathway, can reverse metaplasia in an animal model. Currently they are attempting to reverse or regress precancerous changes in a laboratory model of human tissue they developed and which they call a “mini-metaplastic stomach.”
Based largely on this work, Choi, co-author James Goldenring, MD, PhD, and other VUMC investigators were included in a global effort that earlier this year received a $26 million Grand Challenge Grant from the United Kingdom-based charity Cancer Research UK to develop strategies for preventing and treating inflammation-based cancers including gastric cancer.
Goldenring, the Paul W. Sanger Professor of Experimental Surgery and professor of Cell & Developmental Biology, said he and his colleagues hope to launch a clinical trial this year of a MEK inhibitor “to see if we can reverse metaplasia” in gastric cancer patients in Korea, Japan and Canada.
The paper’s co-first authors were Vanderbilt postdoctoral fellow Jimin Min, PhD, and graduate student Paige Vega. Other contributors included Vanderbilt’s Ken Lau, PhD, associate professor of Cell & Developmental Biology, and Scott Magness, PhD, associate professor at the University of North Carolina at Chapel Hill.
The research was supported by a Career Development Award to Choi and an IDEA Award to Goldenring from the Congressionally Directed Medical Research Program of the U.S. Department of Defense and by grants from the American Association for Cancer Research, the American Cancer Society, the U.S. Department of Veterans Affairs and the National Institutes of Health.