Stanford Cancer Institute News

Spring 2018

Photo courtesy of Ramon Whitson

Understanding why cells such as the one above are resistant to vismodegib is leading SCI researchers to develop new approaches for treating advanced basal cell carcinomas.

Drug Development from Bench to Bedside

A Precision Approach to Skin Cancer

Today, if you’re one of the millions of Americans a year diagnosed with basal cell carcinoma (BCC), you’ll likely get a quick surgery to remove the tumor, which might resemble a shiny bump or reddish patch on your head or neck. If you’re one of the unlucky few for whom the cancer returns or spreads, you’ll be prescribed a targeted drug that helps shrink the tumor—but it might only be a matter of time before your tumor develops resistance to the drug and starts growing again.

At Stanford, a team of researchers that spans dermatology, basic science, and clinical science is piecing together the molecular details of basal cell carcinomas—not only the most common skin cancer, but the most commonly diagnosed of all cancer types. By revealing the cancer’s strategies for survival, they’re assembling new, personalized paradigms to treat the advanced basal cell carcinomas that evade conventional treatment.

 “After initial therapy, you can see escapee tumors easily because they reappear on the skin; it provides us with an amazing teaching tool on all the ways cancers can evolve and avoid getting killed,” said Anthony Oro, MD, PhD, a Professor of Dermatology and an SCI member. “This simple and visible tumor really is instructing us and giving us enormous insight into other cancers.”

In the 1990s, Oro was part of the team that discovered the connection between BCC and a cellular pathway called Hedgehog. In embryos, the Hedgehog pathway—a whole cascade of molecules that interact one after the other like a row of dominoes— directs when and where many types of cells develop. (The pathway was named because fruit fly larva lacking the Hedgehog signaling molecule develop abnormally and resemble spiky hedgehogs). In adults, the Hedgehog pathway helps encourage the proliferation of cells from stem cells, coaxing hair to grow, for instance. But Oro and his colleagues discovered that the pathway was also inappropriately activated in more than 90 percent of BCC cases, spurring the skin’s deep layer of basal cells to grow uncontrollably.

From there, pharmaceutical companies jumped on the discovery and began developing drugs to block key steps in the Hedgehog. One notable development was Genentech’s vismodegib as a treatment for BCC, which the Food and Drug Administration approved in 2012.

“The drug is amazing,” said Oro. “It really melts away the cancers, but the problem is that these resistant clones re-appear.”

So Oro, in collaboration with other Stanford researchers and clinicians including Jean Tang, MD, PhD, an Associate Professor of Dermatology and an SCI member, began isolating samples of the tumors that were resistant to vismodegib and studying how they were managing to survive. The advanced BCC tumors, it turned out, had a variety of ways to turn the Hedgehog pathway back on, even in the presence of the drug. The last step, or final domino, in the Hedgehog pathway—a protein called Gli—needs to be turned on for BCCs to grow. Since vismodegib targets one of the early steps in the Hedgehog pathway, the cancer can activate the pathway again with mutations in proteins that play later roles, flipping Gli back on.

In late 2016, Oro, Tang, and their colleagues reported a collection of mutations in one particular Hedgehog pathway protein that led BCCs to escape treatment with vismodegib. More recently, they’ve identified a pair of proteins called serum response factor (SRF) and megakaryoblastic leukemia 1 (MLK1) that can directly turn up the cell’s production of Gli, even in the presence of vismodegib. In a paper published in the February 2018 issue of Nature Medicine the team reported that nearly half of all BCCs take advantage of this SRF/MLK1 duo and that drugs blocking MLK1 can effectively stop the growth of those cancer cells.

“If we can know how a tumor is going to evolve based on some of these common resistance pathways, then we can be ready with second line therapies and third line therapies and fourth line therapies,” said Tang. “That means we can convert a deadly killer tumor to one that’s handled with chronic treatment where we’re always staying one step ahead.”

While findings on the basic science of cancer often point toward drug targets for which there are no current remedies, the researchers studying BCC have been lucky to pair many of their discoveries with either drugs that already exist, or small molecules with drug potential. Last year, Oro and Tang collaborated with Atul Butte, MD, PhD, of UC-San Francisco, who has pioneered an approach to combine genetic data on diseases like cancer with large databases of existing drugs. His informatics approach, combined with the knowledge the Stanford team already had on the genetic underpinnings of BCC, pointed them toward another combination of existing drugs—including one that interacts with Gli—which can shut off the Hedgehog pathway in BCC cells.

The progress that the SCI team is making regarding BCC’s strategies to activate the Hedgehog pathway are paving the way toward personalized treatment plans for this common cancer, the researchers said. Tang and Oro envision a future where anyone with advanced BCC can have their tumor genetically studied. Then, the right combination of drugs can be selected to shut off their individual cancer. It’s a goal that researchers have for many cancer types but is one that seems closer to reality for BCC, they said. That’s in part due to how accessible and visible the cancer is—it’s easy to biopsy for genetic sequencing— and in part due to vast amounts of research by the Stanford group.

“Basal cell carcinomas are very useful for helping us understand how personalized cancer therapies could work across the board,” said Tang.

The team attributes the success of their work to not only a long history studying BCC, but also to a vertically integrated program at Stanford that includes basic scientists, clinicians, and ties to industry.

“It’s rare to have this sort of extensive, comprehensive program around a single cancer type, and it’s going to teach us how to implement other programs in the future,” said Oro.

Other faculty members involved in the BCC Consortium at Stanford include Anne Chang, MD, Associate Professor of Dermatology and SCI member; Kavita Sarin, MD, PhD, Assistant

Professor of Dermatology and SCI member; Sumaira Aasi, MD, Clinical Professor of Dermatology and Plastic and Reconstructive Surgery; and Tyler Hollmig, MD, Clinical Associate Professor of Mohs and Dermatologic Surgery.