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Study seeks to reverse precancerous stomach lesions

May. 4, 2017, 9:10 AM

Vanderbilt University Medical Center cancer researcher James Goldenring, M.D., Ph.D., has received a two-year, $200,000 grant from the DeGregorio Family Foundation in Pleasantville, New York, to begin clinical trials of a potential approach for reversing precancerous stomach lesions.

James Goldenring, M.D., Ph.D.

Stomach cancer is the fourth leading cause of cancer-related deaths worldwide after lung, liver and colorectal cancers. In the United States, 28,000 people will be diagnosed with stomach cancer this year, and nearly 11,000 will die from the disease, according to the American Cancer Society.

Goldenring said the grant will support an international collaborative trial with colleagues at Yonsei University Medical Center in Seoul, Korea, to test the effectiveness of the drug Selumetinib to reverse pre-cancerous lesions in patients following endoscopic resection of stage I gastric cancer.

Koreans have one of the world’s highest incidences of gastric cancer.

“I am extremely grateful for the support that we have received from the DeGregorio Family Foundation,” said Goldenring, the Paul W. Sanger Professor of Experimental Surgery. “It is often difficult to obtain support for trials that require clinical collaboration at international sites.”

“We are very excited to partner with Dr. Goldenring and his colleagues at Vanderbilt University,” said Lynn DeGregorio, president of the DeGregorio Family Foundation. “We look forward to the day when we can say we had a part in eradicating stomach cancer.”

The foundation was established in 2006 after a 10th member of the DeGregorio family succumbed to stomach cancer and was found to have had a rare gene mutation that causes the disease and other common cancers.

Selumetinib blocks MEK, an enzyme downstream of Ras, a signaling protein that regulates cell growth and survival. Abnormal Ras activation, possibly triggered by other signaling molecules, is associated with up to one-third of all human cancers and recently was identified in a large percentage of gastric cancers.

A year ago, Goldenring reported in Gastroenterology that Selumetinib, a drug recently approved for use in patients with advanced thyroid cancer, halted and reversed neoplastic progression in a mouse model of activated Ras induction of metaplasia and precancerous lesions in the stomach.

It appears that underneath the abnormal metaplastic cells hides a lineage of normal progenitor cells, which can regenerate the normal mucosal layer of the stomach, Goldenring said. When the consequences of abnormal Ras activation were blocked by Selumetinib, normal cells pushed the abnormal tissue out of the mucosa.

The grant will support a study of MEK inhibition in patients who have had local endoscopic removal of a stage I gastric cancer. These patients have a 2 to 5 percent per year incidence of developing a second cancer in the stomach because a large amount of metaplastic mucosa remains.

Astra-Zeneca Corp. will provide the Selumetinib for the trial.
Few clinical trials have focused on the elimination of discrete precancerous cells through drug treatment, Goldenring said.

The protocol for treatment with Selumetinib will evaluate the drug’s efficacy for resolving pre-cancerous metaplasia in humans.

If short-term treatment with Selumetinib is successful in these patients, broader studies will be needed to evaluate the consequences on both cancer recurrence and long-term survival, he said.

Goldenring is professor of Surgery and Cell & Developmental Biology, vice-chair for Surgical Research in the Section of Surgical Sciences and co-director of the Epithelial Biology Center at Vanderbilt University Medical Center.

He also is a staff physician at the Veterans Affairs Medical Center (Tennessee Valley Healthcare System, Nashville campus).

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