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Faculty Focus

Ethan Dmitrovsky, M.D.: A people person

By Laura Stephenson Carter

Ilove you daddy," proclaim the chalk letters scrawled on a blackboard in Ethan Dmitrovsky's office. Dmitrovsky may be a busy physician-scientist—he's the chair of DMS's Department of Pharmacology and Toxicology, nationally recognized for his work, active in countless professional organizations, and the head of a busy lab— but he always has time for the people in his life: his wife and four children; his friends; and his colleagues, especially those in his lab.

Dmitrovsky exudes the calmness, patience, and kindness of a wise teacher. And he creates an environment in his lab that brings out the best in people—ensuring that they get as much satisfaction out of doing research as he does.

"He has a very genuine quality in his interactions with people in the lab that [attests to] his great interest in both his research and his pupils," says Neil Desai, a Dartmouth College '05 who worked in Dmitrovsky's lab as an undergraduate Presidential Scholar. "With that kind of environment in place," adds Desai, now a medical student at Yale, "it's easy to enjoy what you do."

It's clear that Dmitrovsky enjoys all aspects of his work—from hashing out thorny questions in the lab to mentoring young scientists to interacting with peers nationally. And he instills enthusiasm and a sense of purpose in those around him. He also takes pride and pleasure in the fact that what he does is in service to others—patients, DMS, and medicine as a whole.

For example, when asked by Dartmouth President James Wright to be acting dean of the Medical School in 2002-03, Dmitrovsky agreed "out of a sense of service." But he didn't want to be considered for the permanent job because that would take him away from his research and his ability to "participate in the life sciences revolution."

The purpose of scientific discoveries "is to serve the public good," Dmitrovsky firmly believes. For nearly 20 years—previously at Memorial Sloan-Kettering Cancer Center, where he worked from 1987 to 1998, and since then at DMS—his lab has been investigating the role that retinoids, natural and synthetic derivatives of vitamin A, play in treating cancer. Retinoids help regulate cell growth and differentiation. Vitamin A deficiency has been associated with the

In the lab he runs, the department he chairs, and the committees he heads, Ethan Dmitrovsky sets a tone that combines infectious enthusiasm with a sense of purpose.

development of lung cancer in laboratory studies. It would stand to reason, he theorized, that rectifying that deficiency might be a way to prevent lung cancer. But clinical trials with retinoids were, for the most part, unsuccessful in preventing lung cancer in smokers.

While he was still at Sloan-Kettering, Dmitrovsky's lab was the first in the nation to report that retinoids triggered remission in a rare but lethal form of cancer—acute promyelocytic leukemia. He and colleagues identified the biochemical pathway by which retinoids could regulate the cell cycle, helped clone an abnormal receptor linked to the rare leukemia, and developed a molecular test to diagnose the disease. That work led him to explore new ways to treat and perhaps prevent lung cancer, which he describes as "the most lethal malignancy for men and women in our society."

At Dartmouth, his team found a retinoid mechanism linked to lung cancer prevention and identified a retinoid target gene that triggers cell death. In November 2005, he and colleagues published a report in the Journal of the National Cancer Institute (JNCI) that identified a previously unknown retinoid receptor. Targeting it, the researchers hypothesized, may restore the beneficial effects of retinoids in lung cancer cells.

"It turns out that that receptor is repressed in lung cancers," explains Dmitrovsky. "So the drug we were studying—retinoic acid—couldn't possibly work in this disease because of this defect. We knew that a related drug to retinoic acid, called a rexinoid, would be able to activate this same protein destruction pathway, but could bypass this defect that we hypothesized would exist. So about three years ago, we began working on a clinical trial here at Dartmouth to use a rexinoid in conjunction with a second drug called Tarceva." This combination of drugs was tested in a Phase I clinical trial on 24 patients, for most of whom other treatments had failed. Phase I trials seek to determine the maximum tolerable dose of a drug. Although "the expected median survival in this cohort of patients would be about six and a half months," says Dmitrovsky, "the median survival for this trial was over 14 months." A corroborative Phase II trial is under way at DHMC, in collaboration with investigators at Mount Sinai Hospital in New York City.

"We are also studying this regimen in the laboratory, trying to see whether this could be used to prevent lung tumors," continues Dmitrovsky. "This is an example of bidirectional translational research— work from the bench to the clinic and then back again. The appeal of being a physician-scientist is the ability to

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Laura Carter is the associate editor of Dartmouth Medicine Magazine.

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