Why Tumors Relapse When Medications Stop

What happens when the most common and least threatening cancer becomes complicated?

A new study has pointed out a mechanism to control how basal cell cancer responds to treatment and provides new ideas for controlling this disease.

Basal cell carcinoma is very common. About 1 million to 3 million people are diagnosed every year, but few of them are in danger. They are usually surgically removable. But for a small group of patients, this may be a bigger problem.

In some cases, cancer cannot be surgically removed. Medications are then used as treatment.

But there is a problem: when a patient stops taking this medicine, cancer will often recur at the same place.

“This is a very effective drug, but many patients will insist on using it for life,” said Dr. Sunny Wong of Michigan Medical. “We believe that vismodegib brings a subset of tumor cells into dormancy, and they neither grow nor die.”

In a study published in Cancer Cell, researchers described two types of cell populations in basal cell tumors. The outer edge of the tumor is covered with cells and persists even when the Hedgehog gene is blocked. On the other hand, the probability of cell death in the inner cell during vismodegib treatment is three times that of the former.

“What’s most fascinating is that the relative location of tumor cells has a great influence on the sensitivity of drug therapy,” said Dr. Markus Eberl, lead author of the study.

The difference is how the Notch pathway and how each cell activates it. Higher levels of Notch were detected in the inner cells while the outer cells had lower Notch levels. When the researchers completely closed the incision, the tumor was more likely to persist despite vismodegib treatment. When they opened the gap, the tumor narrowed. This work was done with rats.

The outer cells were fixed on the basement membrane of the tumor where the Hedgehog gene signal was high and the Notch signal was low. The researchers explained that this model allows cancer cells to be largely dormant, and patients take the way that hedgehogs suppress the virus. Once drug treatment is stopped, the dormant cells are reactivated.

Notch plays a key role in normal skin and is the most common mutation in skin cancer, seen in up to half of patients.
Only 1% of basal cell tumor patients require vismodegib.

“The side effects of vismodegib are not life-threatening, but there are some concerns,” Wong said. Many patients lose their taste, muscle cramps, weight loss and fatigue. Side effects drive some patients to stop using drugs.

Drug resistance and tumor persistence are problems that block treatment. This is the first study to persevere and explain how drugs work.

Eberl said: “Eliminating stubborn tumor cells is necessary for patients who have a strong therapeutic effect on basal cell carcinoma.”

The researchers said that the key may be to develop a drug that can alter the structure of the tumor so that long-lasting external cells are more like internal cells.

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