Notch Signaling and Treatment With Vismodegib in Basal Cell Carcinoma
A study by Eberl et al in Cancer Cell has pinpointed a mechanism that controls how basal cell cancers respond to treatment and offers new ideas for controlling this disease.
Basal cell carcinomas are incredibly common—somewhere between 1 million to 3 million diagnosed each year—and rarely life-threatening. They are most often removed through surgery, but in some cases, the cancer cannot be surgically removed, often because of where it is found. A small portion of patients have an inherited condition called basal cell nevus syndrome, or Gorlin syndrome, which causes hundreds of basal cell tumors to develop over their lifetime.
Vismodegib (Erivedge), developed to target a key signaling pathway in basal cell carcinoma—the Hedgehog pathway—is a treatment for the disease. However, when patients stop taking the drug, the cancer often recurs at its original site.
“It's a very effective drug, but many patients have to stay on it for their entire life,” explained Sunny Wong, PhD, Assistant Professor of Dermatology and Cell and Development Biology at Michigan Medicine. “We think vismodegib drives a subset of tumor cells into a state of dormancy, where they neither grow nor die.”
He added, “The side effects of vismodegib are not life-threatening, but there are concerns.” Many patients experience loss of taste, muscle cramps, weight loss, and fatigue. The side effects drive some patients to discontinue the drug.
Role of Notch
In the study, researchers describe two types of cell populations in basal cell tumors. The outer edge of the tumor is lined with cells that persist even in the face of Hedgehog blockade. The inner cells, on the other hand, are about three times more likely to die with vismodegib treatment.
“What was most fascinating was that the relative location of a cell within a tumor can have such a big effect on its sensitivity to drug treatment,” said lead study author Markus Eberl, PhD, a former postdoctoral fellow at Michigan Medicine.
The difference stems from the Notch pathway and how each type of cell activates it. Notch plays a key role in normal skin and is the most common mutation in skin cancers, seen in up to half of patients. In a preclinical study, higher levels of Notch were detected in the inner cells, whereas the outer cells had lower levels of Notch. When the researchers shut off Notch completely, tumors were more likely to persist despite vismodegib treatment. When they turned on Notch, tumors shrank.
The outer cells are anchored to the tumor’s basement membrane, where Hedgehog signaling is high and Notch signaling is low. The researchers explain that this pattern allows cancer cells to persist in a largely dormant state while the patient takes the Hedgehog-inhibiting vismodegib. Once the drug treatment stops, the dormant cells reactivate.
Drug resistance and tumor persistence are both challenging issues with Hedgehog-blocking treatments. This is the first study to address persistence and explain how the drug works and, in some cases, falls short.
The researchers suggest the key might be in developing a drug that changes the tumor architecture so the persistent outer cells respond more like the inner cells. Additional research underway is exploring the mechanisms of why Notch affects cell death, searching for proteins or molecules that may be at play.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
