May 18, 2007

Thrill of discovery led to life of research

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Vanderbilt’s Robert Coffey Jr., M.D., delivers last week’s Discovery Lecture.
(photo by Susan Urmy)

Thrill of discovery led to life of research

During his gastroenterology fellowship at the Mayo Clinic, Robert Coffey Jr., M.D., was expected to complete one year of laboratory-based research.

“With absolutely no lab experience, I was very fortunate that Hal Moses accepted me into his lab,” Coffey told the crowd gathered for last week's installment of the Discovery Lecture Series.

And the rest, as they say, is history.

“Much to my surprise, I became totally enthralled by the research enterprise … I found the iterative process of discovery addicting,” said Coffey, Ingram Professor of Cancer Research and director of the GI Cancer Program within the Vanderbilt-Ingram Cancer Center.

Together, Coffey and Moses, M.D., director emeritus of Vanderbilt-Ingram, discovered that transforming growth factors alpha and beta (TGF-alpha and TGF-beta) were produced by normal epithelial cells, not just cancer cells as had been previously believed.

“We predicted that a feature of the malignant process might be loss of the growth inhibitory effects of TGF-beta signaling and accentuated TGF-alpha stimulatory signaling, and time has borne out this prediction.”

Coffey joined the Vanderbilt faculty in 1986, and he has continued to focus on TGF-alpha and its roles in normal physiology and cancer. In early work, Coffey and colleagues noted high levels of TGF-alpha in the stomach and colon and carefully characterized the cell types expressing this growth factor.

“What we're calling normal stomach is really the stomach of either a young Dan Beauchamp or myself,” Coffey said, “so back in those days we would take turns being endoscoped and harvesting tissue that we considered normal. I suspect that today this would be considered a HIPAA violation.”

Coffey and colleagues showed that TGF-alpha could stimulate gastric epithelial growth, inhibit acid production, and increase mucin production.

They implicated overproduction of TGF-alpha in the pathogenesis of Ménétrier's disease, a rare premalignant overgrowth state of the stomach for which there has been no effective medical therapy. Based on their preclinical work, Coffey and colleagues obtained compassionate use approval to treat one Ménétrier's disease patient with cetuximab (Erbitux), a monoclonal antibody that blocks TGF-alpha binding to the epidermal growth factor (EGF) receptor. Cetuximab is approved for the treatment of advanced colorectal cancer.

The marked improvement of this single patient led to an ongoing clinical trial. Of six Ménétrier's disease patients treated to date, “all of them have had dramatic clinical and biochemical improvement,” Coffey said.

“I want to make the point that there is merit in studying a rare disease,” he said. “Our work provides an example of how when we begin to understand the pathogenesis of a disease we can fashion effective therapies.”

In other studies, Coffey and colleagues have characterized the trafficking of EGF receptor ligands to distinct domains of polarized epithelial cells, such as those lining the gastrointestinal tract. They discovered that a protein called Naked2 is required for the efficient delivery of TGF-alpha to the cell surface. Naked2 is lost in 60 percent to 70 percent of colorectal cancers, Coffey said.

“We think that TGF-alpha normally maintains epithelial homeostasis, and when that gets disrupted … there is the opportunity for other ligands to engage the (EGF) receptor, which may contribute to various aspects of tumor progression,” he said.