A recently approved drug for the most common type of skin cancer has been a mixed blessing for patients.

"These new, highly targeted therapies work really well," said dermatology professor Anthony Oro, MD, PhD, who was one of several Stanford researchers involved in the multiyear effort that brought vismodegib to market in 2012. "But this type of treatment is a race against evolution. Within a year, many of the tumors recur when the cancers become resistant to the inhibitor."
The effect on patients, particularly those with a severe condition called Gorlin syndrome, is a heartbreaking yo-yo as the tumors that cover most of their bodies disappear within weeks, but often recur in force.
But Oro and his colleagues' discovery of another, previously unknown component of the Hedgehog pathway — a component vital to its cancer-causing ability — could address this problem. Blocking the activity of this protein, called aPKC, can stop the growth in mice of transplanted skin tumors and tumor cells resistant to vismodegib. The finding, which will be published Feb. 28 in Nature, may pave the way to a future in which cancers are treated with more than one specifically targeted drug.
"Although these tumors evolve in response to targeted drug treatment, we believe there's a limited number of ways they can escape these therapies," said Oro. "If we were able to hit them at the time of diagnosis with drugs that target more than one step in the pathway, they may be less able to evade treatment. We've identified a new target in the Hedgehog pathway and we've developed an inhibitor of this target that we hope will work in human cancers."
Oro, who is the senior author of the study, was also one of several authors on a series of three papers in the New England Journal of Medicine last June describing the effectiveness of vismodegib in treating the most common type of skin cancer, basal cell carcinoma. Postdoctoral scholar Scott Atwood, PhD, is the lead author of the current study.
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"Our goal is to provide precision cancer care at the time of diagnosis," said Atwood. "We're working toward developing better, more specific single and combination therapies to reduce the chance of resistance through tumor evolution."
That work led to the development of vismodegib, which blocks a protein called Smoothened, or Smo, that acts near the beginning of the Hedgehog pathway. Smo sits in the cell membrane and sends signals into the interior of the cell. When activated, it initiates a biological cascade of signaling molecules that culminates in the cell's nucleus at a protein called Gli, which governs gene expression.
Oro and Atwood discovered another, previously unknown protein player in the Hedgehog pathway called aPKC. This protein perpetuates Gli's ability to transcribe, or activate, certain genes by giving it a specific molecular tag (a process called phosphorylation). The phosphorylated Gli in turn goads aPKC to higher levels of activity in what's known as a positive feedback loop.
The researchers studied human skin cancer cells removed from patients and grown in a laboratory dish. They also used a model in which basal cell carcinomas were transplanted onto mice. They looked at levels of aPKC activity and gene expression profiles in the tumors.
"We've found that aPKC is highly active in human basal cell carcinomas that have become resistant to vismodegib," said Atwood. "This positive feedback with aPKC allows tumors to grow really well even in the presence of vismodegib."
When the researchers used an aPKC inhibitor to treat mice bearing transplanted tumors or tumor cells resistant to Smo inhibitors, the growth of the cancer cells was suppressed and the tumors shrank.
The researchers are now working to optimize the selection and design of the aPKC inhibitor. They are also interested in exploring its effect in other cancers in which the Hedgehog pathway is implicated.
"There are a host of Hedgehog-dependent cancers," said Oro, "and we have many researchers and clinicians here at Stanford poised to conduct clinical trials of these types of therapies. It's very exciting."
Source-Eurekalert