A research team led by Sheri Holmen, Ph.D., investigator at Huntsman Cancer Institute and professor in the Department of Surgery at the University of Utah (the U), is testing a new combination drug therapy that could both treat and prevent melanoma metastasis, or spreading from its original site, to the brain.

The research is published in the journal Cell Reports Medicine.

“Once melanoma has spread to the brain, it’s very hard to treat. Metastasis to the brain is one of the main causes of death from melanoma,” says Holmen. “We wanted to find a solution to an unmet clinical need for those patients who had no other treatment options available, and this is a huge step forward.”

Holmen and her team first examined what causes melanoma cells to spread to the brain and identified focal adhesion kinase (FAK) as a potential target for new therapies. FAK is an enzyme that regulates cell growth, and, they found, is a major contributor to melanoma metastasis.

If caught early, melanoma can be treatable with surgical removal. But once the disease has spread beyond the skin to other organs, it becomes more difficult to treat—and more fatal.

Immunotherapy, using a patient’s own immune system to attack cancer cells, is often the first line of treatment for advanced melanoma patients. But, Holmen says, this treatment doesn’t work as well once the tumor has spread to the brain. There are also targeted drug therapies that people take orally as a pill.

“Patients can become resistant to those drugs over time. And once the disease has reached the brain, they also don’t work as well,” says Holmen.

“The window of time to treat a patient with brain metastasis is shortened quite significantly because the average survival from time of diagnosis of brain metastasis is only about a year—even while using these other therapies.”

Holmen and her research team found that inhibiting the enzyme FAK in combination with an inhibitor of RAF and MEK—which targets another cellular pathway that regulates cancer cell growth—was effective in prolonging survival rates in preclinical mouse models. They specifically studied a subtype of melanoma triggered by a mutation of BRAF, a gene that helps regulate cell division.

A mutation of this gene has been identified with several types of cancer, including an estimated 50% of patients with metastatic melanoma.

“This combination drug therapy also stopped the development of brain metastasis, and that’s where this research is very exciting,” says Holmen. “Not only did it treat the tumor once it had spread and was growing in the brain, it also prevented the cells from getting there in the first place.”

The oral treatment combines two drugs: defactinib, which blocks a protein called FAK, and avutometinib, which blocks proteins called RAF and MEK. This combination therapy could make treatment more accessible for melanoma patients who have difficulty traveling long distances. Melanoma rates are consistently high in states across the Mountain West, the area Huntsman Cancer Institute serves.

“Receiving a treatment like immunotherapy requires an infusion, and patients have to travel to a hospital or clinic for that kind of specialized treatment,” says Holmen. “Having oral drugs available will increase treatment options for our patients, especially those living in rural and frontier areas.”

The study, led by Howard Colman, MD, Ph.D., professor in the Department of Neurosurgery at the U, has now moved into clinical trials for patients at Huntsman Cancer Institute and Holden Comprehensive Cancer Center at the University of Iowa.

The study is open to patients with melanoma with brain metastases.