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A new study pinpoints a mechanism that controls how basal cell cancers respond to treatment and offers new ideas for controlling the disease. Basal cell carcinomas are common, they’re often removed through surgery. In some cases, the cancer cannot be surgically removed, often because of where it’s 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.
An early success story among targeted therapies, developed to hit a key pathway in basal cell carcinoma called Hedgehog. By blocking Hedgehog, the cancer cells die but when patients stop taking the drug, the cancer often grows back at the same site. Many patients have to stay on it for their entire life. 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 undergo cell death from vismodegib treatment.
The relative location of a cell within a tumor can have such a big effect on its sensitivity to drug treatment. The difference stems from the Notch pathway and how each type of cell activates it. Higher levels of Notch were detected in the inner cells, while 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 work was done in mice.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 re-activate.
The side effects of vismodegib are not life-threatening, many patients experience loss of taste, muscle cramps, weight loss and fatigue. The side effects drive some patients to discontinue the drug. Drug resistance and tumor persistence are both challenging issues with Hedgehog-blocking treatments. Eliminating persistent tumor cells is necessary to cure patients who have tough-to-treat cases of basal cell carcinom.
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