Randa Iskander traveled from Lebanon to VUMC to take part in the study. (photo by Joe Howell)
New treatment reverses rare stomach disorder
Randa Iskandar of Hermel, Lebanon, was in her mid-70s when she started having bouts of extreme stomach pain and uncontrolled vomiting. Over the next year and a half, she lost nearly 40 pounds.
Doctors in her home country told her she might have Ménétrier's disease, which causes overgrowth of the stomach lining, decreased acid production, excess mucus secretion and edema. Patients are at risk for gastric cancer. There has been no medical treatment for this rare disease and patients often undergo gastrectomy — removal of the stomach — because of debilitating symptoms or concern about cancer.
Iskandar's sons turned to the Internet and found that Robert Coffey, M.D., professor of Medicine and Cell and Developmental Biology, had opened a clinical trial at Vanderbilt to treat Ménétrier's disease with the colorectal cancer drug cetuximab (Erbitux). The results of that trial were published last week in Science Translational Medicine.
Coffey and his colleagues reported that cetuximab, a monoclonal antibody that blocks epidermal growth factor (EGF) receptor signaling, is an effective, first-line treatment for Ménétrier's disease.
“We don't know whether it reduces the likelihood of gastric cancer,” said Coffey, the paper's senior author. Nevertheless, “we have identified the first effective medical therapy for this disorder.”
Investigators involved in the study include, from left, Robert Coffey, M.D., Christa Hedstrom, Ed.D., R.N., and William Fiske, M.D., MPH. (photo by Mary Donaldson)
Nine patients with severe disease who were considering gastrectomy enrolled in the clinical trial.
Two later dropped out but the remainder, including Iskandar, experienced significant relief of symptoms within hours or days after beginning treatment. All seven patients continued taking cetuximab after the monthlong trial ended.
One of Iskandar's sons, Mousa, worked with the U.S. embassy in Beirut to expedite her travel to Vanderbilt for treatment. She speaks no English, so Mousa translated from her native Arabic.
“She did not feel any pain after the first two weeks here and she could put away the cup she had been carrying while she had been vomiting,” he said.
Iskandar was one of four patients who had near-complete remission of the disease. Now 82, she stopped taking the drug after 18 months and remains symptom-free with a normal stomach two years later.
A second patient is off treatment, a third has been taking the drug for nearly four years, and the fourth eventually underwent gastrectomy along with the other three patients in the study.
“Thanks to God and thanks to Dr. Coffey,” Iskandar said through her son. “He is like a brother for what he did.”
The paper's first author is William Fiske, M.D., assistant professor in the Division of Gastroenterology.
Other co-authors are Jarred Tanksley, Ki Taek Nam, Ph.D., James Goldenring, M.D., Ph.D., Robbert Slebos, Ph.D., Daniel Liebler, Ph.D., Amir Abtahi, Bonnie La Fleur, Ph.D., Gregory Ayers, Christopher Lind, M.D., and Mary Washington, M.D., Ph.D.
The study was supported by the NCI-funded GI Special Program of Research Excellence, Mouse Models of Human Cancers Consortium and Vanderbilt's Clinical Translational Science Award.
Coffey’s research key to identifying treatment
by Bill Snyder
Last week's report that a colorectal cancer drug can reverse Ménétrier's disease, a rare stomach disorder, results from two decades of research by Vanderbilt scientists led by Robert Coffey, M.D.
Coffey began studying transforming growth factor-alpha (TGF-a), the key signaling protein that underlies the disease, in the mid-1980s as a gastroenterology fellow in the lab of Hal Moses, M.D., at the Mayo Clinic.
“Investigators initially thought TGF-a was just made by cancer cells, but we demonstrated that it also was made by normal cells,” said Coffey, Ingram Professor of Cancer Research and director of the Specialized Program of Research Excellence in GI Cancer at Vanderbilt-Ingram Cancer Center.
In 1986, Coffey came to Vanderbilt, where he and his colleagues found that, by binding to the EGF receptor in the stomach, TGF-a could induce proliferation of mucous-producing cells, while suppressing acid-producing parietal cells.
By the mid-1990s, they had discovered TGF-a was over-expressed in the stomachs of patients with Ménétrier's disease. Transgenic mice that over-expressed the protein in the stomach also showed “all the histological and biochemical features of the disease,” he said.
With “compassionate-use” approval from the FDA, Coffey and his colleagues next tested an investigational EGF receptor blocker in a 48-year-old man with severe Ménétrier's disease.
“He had intractable nausea and was vomiting 70 times per week,” Coffey explained. “Within hours of the first treatment, he was much improved. At one month, vomiting was reduced to once a week, and (his) parietal cells had returned.”
The drug, cetuximab, was later approved for colorectal cancer. The Vanderbilt report, published in the New England Journal of Medicine in 2000, set the stage for a larger study.
Coffey said the study could not have been done without Vanderbilt's Clinical Research Center or the University's investment in “discovery science.”
Through the Epithelial Biology Center, which Coffey directs with James Goldenring, M.D., Ph.D., researchers will now try to find out what triggers the disease, usually in middle age, and whether there are any genetic risk factors.
Four of the patients in the study also had ulcerative colitis. Is there a connection? That's the value of studying rare diseases, said Coffey.
“You can gain important insights into disease pathogenesis.”