Long research journey leads to promising treatment advances for BCCs, other cancers

Ervin H. Epstein Jr., MD: ‘If you take enough government money and put it into basic research, you will end up with things you can do for people that absolutely would not have been possible otherwise.'

Ervin H. Epstein Jr., MD: ‘If you take enough government money and put it into basic research, you will end up with things you can do for people that absolutely would not have been possible otherwise.’

Clinical trial results show that vismodegib is effective in treating basal cell carcinomas (BCCs) by acting as an inhibitor in the Hedgehog pathway, a breakthrough in the translation of genetic research into therapies to treat cancers.

Dermatologist and researcher Ervin H. Epstein Jr., MD, has been heavily involved in the study of genetic skin diseases since the 1980s and the identification of the PTCH1 gene as a culprit in the development of BCCs in Gorlin syndrome, and other cancers. His Eugene J. Van Scott Award for Innovative Therapy of the Skin and Phillip Frost Leadership Lecture, “Thwacking the Hedgehog,” detailed those developments Sunday.

“Because of Nobel Prize-winning work done two decades earlier in fruit flies, when the patched gene was found to harbor the mutations that cause Gorlin syndrome, it was well known what this gene did,” he said. “It produces a protein that acts as a primary inhibitor of the Hedgehog signaling pathway. Signaling pathways are like the nervous system of an individual cell. They sense the environment, they bring that information to the nucleus, and just as we behave appropriately in accordance with the information about our surroundings, so too does the cell change its behavior based on its sensing of its surroundings.”

When the PTCH gene is abnormal, it wreaks havoc in the Hedgehog pathway signaling and can cause the development of a variety of tumors, said Dr. Epstein, senior scientist at Children’s Hospital Oakland Research Institute, Oakland, Calif. He also was a long-time faculty member at the University of California, San Francisco, and president of the Society for Investigative Dermatology.

“That realization was a big deal because it was one of the first observations that a pathway that is crucial to normal embryonic development also could cause cancers when it went astray in adulthood,” he said. “Indeed, many cancers are caused by dysregulation of such pathways. In 2002-04, data were published suggesting that as many as 25 percent of internal cancers might have aberrant signaling in the same Hedgehog pathway.

“At that time, all self-respecting pharmaceutical companies became interested in developing drugs that would inhibit this pathway, and in maybe treating cancer that way. So, a half-dozen of these molecules from different companies have been in clinical trials.”

The first Hedgehog signaling agent to be tested in humans was vismodegib, in 2007, and the Food and Drug Administration approved its use in 2012 for the treatment of patients who have metastatic or locally advanced BCCs, Dr. Epstein said.

In 2009, the same drug was given to patients with Gorlin syndrome, a heritable disorder linked to the development of large numbers of BCCs. The initial results of the trial were published in the New England Journal of Medicine in June 2013.

“Our double-blind, randomized trial showed that the patients who were taking this drug had, in all fairness, a dramatic response to the drug,” Dr. Epstein said. “It is very clear the drug has quite spectacular inhibitory effects on the growth of basal cell carcinomas in these patients.”

To be involved in the trial of a treatment that has its roots in investigations he started a quarter-century earlier is unusual, especially for someone spending much of his time as a clinical dermatologist, and Dr. Epstein appreciates that rare opportunity.

“I’ve had the great privilege of having been able to participate in the identification of a gene underlying a rare heritable disorder and sticking around long enough to participate in the clinical trial of the drug that replaces the function of the missing gene in the very same syndrome,” he said. “Sixteen years between the identification of the gene and the approval of the drug sounds like an enormously long time, and indeed it is. At the end of the day, something actually came of it.”

Dr. Epstein has long exhibited the patience required in such a journey. He entered the world of research when serving in the U.S. Public Health Service at the National Institutes of Health (NIH) during the Vietnam War.

“I’m a great believer in exposing people to the opportunity to do research, whether they think they are going to do it or not,” he said. “For many of us, it is absolutely a compelling way to spend our lives.

“It’s an indication that if you take enough government money and put it into basic research, you will end up with things you can do for people that absolutely would not have been possible otherwise. It is very clear that the NIH experiment has been one of the high points of our government’s history.”

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