The new treatment for basal cell nevus syndrome, also called Gorlin syndrome, springs from an unlikely location: Idaho’s mountain pastures. In the 1960s and 70s, sheep farmers began noticing that when their flocks grazed at higher altitudes, pregnant ewes would give birth to lambs with a single, central eye. The alarmed sheep farmers called in the U.S. Department of Agriculture, which launched an investigation. It took 11 years to discover that the ewes were grazing on the American corn lily, a mountain meadow plant that contains a chemical that disrupts normal brain and facial development, resulting in the deformities the farmers observed.
Years later, the corn lily chemical—cyclopamine—was determined to be a potent inhibitor of the Sonic hedgehog (Shh) signaling pathway, which is critical for normal fetal development.
“I was also interested in looking at underlying mechanisms and trying to identify therapeutic targets in skin cancers, with the ultimate goal of finding drugs and compounds that could be taken to the clinic,” says Dr. Bickers, who came to Columbia in 1994 with a major interest in skin cancer research. He knew that Gorlin syndrome patients inherit a mutation in a tumor suppressor gene family called patched (PTCH).
PTCH1 was the primary inhibitor of the Shh signaling pathway that was turned off in the cyclops sheep. Normally PTCH1 causes the signaling to cease after birth. But when PTCH1 is mutated, signaling continues, resulting in abnormal cell growth and proliferation and setting the stage for tumor formation. “If we could find a molecule to inhibit this pathway we could, in theory, reverse the growth of the tumors,” says Dr. Bickers.
The right molecule turned out to be cyclopamine, the corn lily chemical. Dr. Bickers, working at Columbia with research scientist Mohammad Athar, PhD, and Arianna Kim, PhD, assistant professor of dermatology, found that while it had disastrous results for the farmers and their flocks, it was precisely what Gorlin syndrome sufferers needed: a way to block the postnatal signaling that led to the unchecked growth of tumors in many patients.
Drs. Epstein and Bickers investigated the use of a vismodegib, a derivative of cyclopamine synthesized by Genentech. Their clinical study found that patients taking the orally administered drug for an average of eight months experienced about two new basal cell cancers during the study, compared with 29 such tumors for patients in the placebo group.
“The purpose of the study was to see whether, using this targeted molecular therapy, we could match the performance of a surgeon, and in many ways, we could,” says Dr. Bickers.
Important issues remain, however, and Dr. Bickers says the drug is not suitable for all patients with basal cell nevus syndrome. The drug caused muscle pain and loss of taste in many patients in the trial, and half of the participants on the drug stopped using it even though that meant their cancers would return.
“The challenge now is to see if we can lessen the adverse effects while achieving the same therapeutic benefits by modifying the dosing schedule or perhaps by alternating drug treatment with other modalities such as photodynamic therapy, which can be effective for smaller lesions.”
This was adapted from an article in the Fall/Winter 2014 issue of Columbia Medicine magazine. Read the full article here.
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