Mouse Avatar May Help Halt Melanoma Progession

A targeted drug that was previously found to be ineffective has shown promise for halting the progression of melanoma, thanks to a new method using avatar mice for patients, according to a recent study.

Melanoma, which accounts for approximately 5% of all incidences of skin cancer, has a 75% mortality rate. The BRAF mutation, which is found in approximately half of all melanoma cases, can cause growth of the disease. This factor provides caregivers with the option of using targeted drugs for treatment.

Unfortunately, the cancer cells adapt to treatment and look for alternative survival mechanisms, which researchers call “escape routes.” This causes patients to eventually become unresponsive to the drugs, leading to relapse.

"There are about 15 routes of escape that we've identified in melanoma patients, and it is never easy to predict which 1 will be used in any given patient," said researcher Meenhard Herlyn, DVM, DSc. "These melanoma cells will do anything to get reactivated."

Researchers are now studying these melanoma escape routes in the hope of cornering cancerous cells with combination treatments that don't allow them to survive.

In the current study, investigators used a method called patient-derived xenograft (PDX) mouse models (avatar mice), where they implant tumor samples from patients to mice. By studying 1 tumor in a group of mice avatars, it allows them to study different drug combinations to see how a tumor will respond.

During the current study, PDX models were used to test tumors from patients who relapsed after treatment with a BRAF inhibitor. In observing mutations in the NRAS and MAP2K1 genes, which act as escape routes for previously treated BRAF mutations, investigators found an increase of MET, a possible new resistance mechanism.

The drug capmatinib, a MET inhibitor, was found to cause temporary signs of tumor regression during recent clinical trials. Since the regression was only temporary, the result indicated that MET was not the only driver of tumor growth.

The combination of capmatininb, encorafenib (BRAF inhibitor), and binimetinib (a MEK inhibitor that hits the BRAF pathway), caused a sustain tumor regression in the mice.

"Historically, MET inhibitors have not shown much activity in melanoma patients," said study author Clemens Krepler, MD. "While our findings need to be validated in more robust trials, this study provides evidence than MET inhibitors given either after or at the same time as BRAF inhibitors appear to successfully halt the progression of the disease and may considerably lengthen response and overall survival in melanoma patients."