New melanoma therapy prevents brain metastasis in preclinical studies
A government-funded research team has identified focal adhesion kinase (FAK) as a key driver of melanoma metastasis to the brain. This discovery could revolutionise treatment by not only addressing the condition but also preventing its spread to the brain.
The research team, led by Dr Sheri Holmen, an investigator at Huntsman Cancer Institute and professor in the Department of Surgery at the University of Utah (the U), is testing a novel combination drug therapy. This therapy has the potential to transform melanoma treatment by both treating the condition and preventing its spread to the brain. Holmen and her team identified focal adhesion kinase (FAK), an enzyme that regulates cell growth and contributes significantly to the disease’s progression, as a key driver of melanoma metastasis to the brain.
“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,” explains 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.”
While early-stage melanoma can often be treated with surgical removal, advanced melanoma that spreads to other organs becomes far more difficult to manage. Immunotherapy, where a patient’s immune system attacks cancer cells, is typically the first line of treatment for advanced melanoma, but its effectiveness diminishes once the disease reaches the brain. Targeted oral drug therapies also exist, but patients can develop resistance to these treatments, making disease management much harder.
Holmen’s research team found that combining an inhibitor of FAK with an inhibitor of rapidly accelerated fibrosarcoma (RAF) and mitogen-activated protein kinase kinase (MEK), two other key regulators of cancer cell growth, significantly prolonged survival rates in preclinical mouse models. Their study focused on a subtype of melanoma triggered by a mutation in the BRAF gene, a mutation that occurs in approximately 50 percent of metastatic melanoma cases.
“This combination drug therapy also stopped the development of brain metastases, and that’s where this research is very exciting,” Holmen says. “Not only did it treat the tumour once it spread to and was growing in the brain, but it also prevented the cells from getting there in the first place.”
This new therapy, developed in collaboration with Verastem Oncology and supported by the National Cancer Institute, has been evaluated in preclinical studies and published in Cell Reports Medicine. The treatment combines two oral drugs: Defactinib, which blocks FAK, Avutometinib, which blocks RAF and MEK. This approach may make melanoma treatment more accessible, particularly for patients in rural areas. Immunotherapy requires hospital or clinic visits for infusions, whereas an oral drug regimen could be taken at home.
“Having oral drugs available will increase treatment options for our patients, especially those living in rural and frontier areas,” Holmen notes. Melanoma rates are consistently high in states across the Mountain West, the area served by Huntsman Cancer Institute.
The study, led by Dr Howard Colman, MD, professor in the Department of Neurosurgery at the University of Utah, has now progressed to clinical trials at Huntsman Cancer Institute and Holden Comprehensive Cancer Centre at the University of Iowa. The trial is open to patients with melanoma brain metastases, offering new hope for those affected by this aggressive disease.
This research was supported by the National Institutes of Health/National Cancer Institute, including grants P30 CA042014 and R01CA121118, along with funding from the Huntsman Cancer Foundation. With the potential to not only treat but also prevent melanoma brain metastases, this innovative therapy could mark a significant advancement in the fight against advanced melanoma.
