New research, published in Cancer Cell, has advanced the understanding of basal cell carcinoma (BCC) cell signaling pathways which could lead to improved treatments for the condition when it is not operable or difficult to treat. BCC is a non-melanoma skin cancer appearing in the form of abnormal growths or lesions on the skin. In general, the lesions are simply surgically removed but can sometimes be in a location too precarious for surgery or are too abundant, as in the inherited condition known as Gorlin syndrome. BCC is usually caused by cumulative sun exposure and generally does not metastasize.
Vismodegib is a small molecular inhibitor drug that is successful at combating BCC by targeting the Hedgehog pathway. The one major drawback is that individuals must stay on the drug indefinitely because the cancer will return once the therapy is stopped. "It's a very effective drug, but many patients have to stay on it for their entire life," says Sunny Wong, Ph.D., assistant professor of dermatology and of 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."
The study revealed that inner cells of BCCs respond to vismodegib treatment but cells on the outer edge of tumors survive even when Hedgehog signaling is blocked with the drug. "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," says lead study author Markus Eberl, Ph.D., a former postdoctoral fellow at Michigan Medicine.
Image: When patients stop taking vismodegib, basal cell tumors often grow back. Image courtesy of Michigan Medicine.
The difference in drug response between the two cell types is related to how each cell type activates the Notch pathway, as seen in mice. The outer cells have contact with the basement membrane where Hedgehog signaling is high and Notch is low. The inner cells have high levels of Notch and low levels of Hedgehog signaling. Elimination of Notch resulted in tumors that continued to grow when treated with vismodegib and, conversely, the tumors shrank when Notch was re-introduced. When Hedgehog signaling is blocked by vismodegib, it seems that the cancer cells become dormant but re-activate once the drug therapy is discontinued.
This is the first study to provide some explanation for drug resistance and tumor persistence, both common and challenging issues with Hedgehog-blocking cancer treatments. The research team is performing further research on Notch’s role in cell death and other molecules involved in the pathway.