Team identifies first drug therapy for rare, precancerous stomach illness

December 06, 2000

Vanderbilt-Ingram Cancer Center scientists have identified the first drug therapy that appears to be effective in reversing the "miserable" symptoms of a rare, premalignant stomach disorder.

They describe the effective treatment of a Texas man's Ménétrier's disease in the Dec. 7 issue of the New England Journal of Medicine. This report culminates 10 years of basic research into the role in the stomach of the epidermal growth factor receptor and one of the factors that binds to it, transforming growth factor-alpha (TGFa). It also opens new avenues for additional research to better understand the biochemical pathways involved in this disease as well as stomach and other cancers.

"This really takes us from bench to bedside and back," said the principal investigator, Dr. Robert Coffey, Ingram Professor of Cancer Research. "It's very gratifying to have worked in an area for more than 10 years, plugging along, and then be able to implicate a pathway that is important in the pathogenesis of a human disease."

First described in 1888, Ménétrier's disease is quite rare. Only 300 cases of what Coffey describes as a "fascinating disease" have been described in the scientific literature, he said. However, Coffey noted that the study of rare diseases often has broader implications. He cited retinoblastoma as an example: the study of this rare disease in children led to the identification of tumor suppressor genes and the "two-hit hypothesis" - the idea that it requires the functional loss of both copies of such a gene to prompt cancer development.

"From rare diseases, we often gain important insight into more common diseases," he said.

Ménétrier's disease develops later in life, often when patients are in their 50s or 60s. Characteristics of Ménétrier's disease include a thickening of the stomach lining and a complete absence of the parietal cells that produce stomach acid. The gastric juice is typically full of mucous, and protein leaks through the stomach lining and is lost in the stool. Patients typically seek medical help because of persistent vomiting and swelling in the legs. No medical treatment has been effective and removal of the stomach is often required for symptom relief and to prevent the progression to cancer.

The 48-year-old Texas man was referred to Coffey from the University of Texas-Southwestern Medical Center in Dallas with endless vomiting - before treatment, he was vomiting an average of 70 times a week. "He was miserable," Coffey said.

However, because of a severe underlying lung disease, he could not undergo surgery. The Food and Drug Administration and the institutional review boards of both academic centers gave "compassionate use" approval for a one-month course of a new drug, a monoclonal antibody that blocks activation of the EGF receptor called C225.

GFa is a cousin to the epidermal growth factor whose discovery won Vanderbilt's Stanley Cohen, Ph.D., a Nobel Prize in Medicine. EGF and TGFa are among six ligands that can activate the EGF receptor, which Cohen also identified with Graham Carpenter, Ph.D., Ingram Professor of Cancer Research and Biochemistry. The EGF receptor is involved in the overgrowth of cells that is characteristic of cancer.

Coffey's laboratory had previously shown that TGFa is produced in the normal stomach, where it stimulates growth of gastric epithelial cells, suppresses acid production and protects against injury to the stomach lining, most likely by increasing mucous levels - all features found in patients with Ménétrier's disease.

To investigate their suspicion that enhanced EGF receptor signalling was a cause, Coffey's team also studied tissue samples from 20 patients with the disease and found excessive amounts of TGFa. Further evidence: mice engineered to overproduce TGFa in the stomach exhibited virtually all the features of Ménétrier's disease.

The effect of C225 in this patient was quick and impressive, the scientists report. "By the day after his first injection, he was already feeling better, which we suspected was a placebo effect," Coffey said.

However, his vomiting virtually ceased, and gastric biopsies taken the day before and after revealed a marked reduction in proliferation of surface mucous cells and an increase in levels of gastrin, which prompts development of acid-producing parietal cells.

After four weekly injections, the patient was studied again. The level of protein in his blood had increased and his stool protein loss fell by two-thirds. The sharp rise in gastrin seen on the day after initial treatment was sustained, and - most remarkably, Coffey says - acid-producing parietal cells reappeared.

Coffey cautioned that the benefit of this treatment must be confirmed in additional patients with Ménétrier's disease and noted that so far, long-term outcome has not been evaluated. This patient died suddenly of a heart attack during evaluation for a heart-lung transplant shortly after his treatment with C225.

The information gathered in this case sets the stage for further laboratory research into the control of development of different types of gastric cells and the regulation of gastrin production. "It seems clear that Ménétrier's disease results because of enhanced signalling of the EGF receptor," Coffey said. "We think it's TGFa, but other ligands for the EGF receptor may also have this effect. We'll now be able to go back to the mouse model and address these issues."
The National Institutes of Health, the Department of Veterans Affairs, the Joseph and Mary Keller Foundation and the Peter Power Memorial Fund supported this research.

The Vanderbilt-Ingram Cancer Center is one of a select few designated by the National Cancer Institute to lead the worldwide fight against cancer. Vanderbilt-Ingram is the only NCI-designated cancer center in Tennessee that treats and conducts research in all types of cancer in adults and children. Its team of more than 1,000 doctors, scientists, nurses and others are dedicated to working together to offer the most promising treatment and prevention strategies, built on a strong foundation of basic research.

Vanderbilt University Medical Center

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