Years of research by Vanderbilt University Medical Center investigators to determine how precancerous cells in the stomach transition to gastric cancer and to develop strategies to prevent this transition have received federal funding to test two potential treatments.
The $2.5 million Department of Defense Translational Team Science Award provides funding over four years to launch a clinical trial in the U.S. with one of the therapies and compare it with another therapy from an ongoing clinical trial in Japan.
James Goldenring, MD, PhD, the Paul W. Sanger Professor of Experimental Research, and professor of Surgery and of Cell and Developmental Biology, is the lead principal investigator. Eunyoung Choi, PhD, associate professor of Surgery and Cell and Developmental Biology, is a co-principal investigator along with Katherine Garman, MD, associate professor of Medicine at Duke University.
The U.S. clinical trial will be conducted under Garman at Duke to evaluate the effectiveness of pyrvinium, an existing medicine that has been used for the past 70 years to treat pinworms in children, for a new purpose — reversing metaplasia of stomach cells and killing dysplastic precancerous cells.
While metaplasia is a reparative process in the stomach lining and is less likely to lead to cancer, dysplasia develops from metaplasia and is considered the critical step toward carcinogenesis. Choi and colleagues have validated that pyrvinium can be repurposed as a preventive treatment for stomach cancer, having previously demonstrated in human organoids and mouse models that the drug induces cell death in precancerous dysplastic lesions.
The ongoing clinical trial in Japan, which is led by Sachiyo Nomura, MD, PhD, in collaboration with Goldenring, is testing a targeted therapy using low dose trametinib, which is an inhibitor of the MEK signaling pathway. MEK, an abbreviation for the mitogen-activated extracellular signal-regulated kinase pathway, plays an integral role in the development of stomach cancer. Pyrvinium also blocks the MEK pathway, the researchers have shown.
Using patient samples from the clinical trial in Japan, they will seek to determine how trametinib is changing cells that line the stomach as well as immune cells and other cell types found in the stomach.
They will compare cell changes from both treatments in the individual patients with the goal of developing personalized or precision preventive strategies.
“These trials are the first ever attempted to utilize directed therapeutic interventions to arrest and reverse precancer as a general strategy for decreasing patient risk for developing gastric cancer,” said Goldenring.
While stomach cancer is one of the three highest causes of cancer-related deaths worldwide, its incidence is lower is the U.S. But it does occur more frequently among minority ethnic groups. The percentages of minorities currently serving in the U.S. armed services is higher than their proportion of the general population. In the U.S. most stomach cancers are diagnosed at late stages when they are more difficult to treat.
Infection of the stomach with the bacteria Helicobacter pylori leads to a loss of acid-secreting cells within the lining of the stomach, and their absence leads to metaplasia, the development of a new set of lining cells.
The overall goal of the study is to develop and implement prevention strategies for stomach cancer for high-risk populations and improve mortality rates from the disease.
“Comparison of patient responses to pyrvinium in patients with those in patient-matched 3D cell culture models established from enrolled patient biopsies will provide a feasibility of prediction of clinical drug responses,” said Choi.