New insights on a skin cancer drug

An explanation for resistance

Five years ago, Winnie Bazurto was on the verge of losing vision in her right eye because of a fast-growing tumor on her lower eyelid. Normally, the type of cancer she had, basal cell carcinoma, would have been treated with surgery or radiation. But because of her age, Bazurto, nearly 100 at the time, was a special case. She got what was then a special treatment: a new skin cancer drug. [Read more of Bazurto’s story in our Summer 2013 issue.]

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The drug, vismodegib, was the first drug approved by the U.S. Food and Drug Administration to treat advanced basal cell carcinoma, the most commonly diagnosed cancer in the United States.

Cancer, however, works hard to stay alive, to find ways to return. Though the drug is holding Bazurto’s cancer in check, in about 20 percent of patients it recurs in a few months. Now a team of Stanford researchers has identified exactly how the cancer gets past vismodegib’s ability to block what they knew to be the key enabler of the cancer’s growth — untimely activation of the Hedgehog molecular signaling pathway.

Like other signaling pathways (hundreds of which exist in living organisms), the Hedgehog pathway is a cascade of protein interactions, with one protein activating the next, in a chain reaction of sorts. Vismodegib, sold under the brand name Erivedge, binds to and inactivates a protein called Smoothened, one of the Hedgehog pathway’s first steps.

Recognition of the importance of the Hedgehog signaling pathway dates back to the 1970s, when scientists studying the biology of development from single egg to complex organism discovered its role in determining the body plan of the fruit fly. In humans, the pathway is also important for normal development. In 1996, a team of Stanford and UC-San Francisco scientists made the connection between this signaling pathway and cancer: They found malfunctions in the pathway could cause basal cell carcinoma.

The latest round of discoveries at Stanford found a pattern in how Smoothened proteins were mutating to develop resistance to vismodegib. They also found that they could use another class of drugs called Gli inhibitors to block the Smoothened mutation downstream.

This new entry in the encyclopedia of Hedgehog signaling pathway behavior is a big step in genomics-driven medicine, says Stanford vismodegib researcher and Bazurto’s dermatologist, Jean Tang, MD, PhD. The same pathway is central to the development of other cancers, including some of its most lethal forms: non-small cell lung cancer, ovarian cancer, certain types of leukemia, the bone marrow disorder myelodysplastic syndrome and the most common malignant brain cancer — medulloblastoma.

Now, these researchers are building a database of skin cancer biopsies to build a profile of each patient’s cancer, identifying which mutations are its engines and which currently available drugs can counteract them.

Bazurto will be 104 years old this August. She’s a bit frail, of course, but one problem she doesn’t have is poor vision. Watching football and baseball on television is one of her great joys, she says. And she’s still at it.

Sara Wykes is a writer for the Stanford Hospital & Clinics communications office. Email her at swykes@stanfordhealthcare.org.

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