What they found was that melanoma cells are more likely to metastasize through the body if their cells have high concentrations of MCT1 on their cell surface.
Melanoma is the worst form of skin cancer, accountable for 1% of skin cancer cases, but the cause of the vast majority of skin cancer deaths. In 2019, the AIM at Melanoma Foundation estimated there were 96,480 new cases of melanoma in the U.S. and 7,230 deaths from the disease.
The disease can be quite variable. In some cases, the cancer cells stay in the skin and never metastasize to the blood and on to vital organs. Others, if they do get past the skin and into the blood, don’t make it past the lymph nodes. But in some patients, the cancer cells enter the blood, get past the lymph nodes and into vital orders such as the brain or lungs. Why there’s so much variability has been largely a mystery.
Now, investigators from the University of Texas Southwestern Medical Center in Dallas and the University Duisburg-Essen in Germany published research in the journal Nature describing mechanisms explaining the process.
What they found was that melanoma cells are more likely to metastasize through the body if their cells have high concentrations of MCT1 on their cell surface. MCT1 appears to gather lactate in the blood, deliver it into the cancer cell and increase its likelihood of survival.
Working with laboratory mice, the UT Southwestern researchers injected the animals with human melanomas that had high or low concentrations of MCT1. The animals receiving the cells with high levels of MCT1 were more likely to metastasize, while the animals receiving cancer cells with low levels of MCT1 were less likely to have metastases.
Sean Morrison, of the Children’s Medical Center Research Institute at U of T Southwestern led the research. Morrison told STAT, “If I had melanoma, I’d want to know my MCT1 status.”
The next step in the research was to give the laboratory animals implanted with human melanomas a dose of AstraZeneca’s investigational drug AZD3965, which blocks MCT1. What they found was the animals had fewer melanoma cells in the blood with fewer cases of metastasis.
“Inhibiting MCT1 doesn’t have much effect on the primary tumor or on established metastases,” Morrison told STAT. But for cells that are between those two states, it “can prevent metastasis” and prolong survival in the mice.
AstraZeneca is currently running a Phase I clinical trial of AZD3965 in patients with advanced solid tumors. Morrison believes that’s too late, that the drug and its oxidative stress activity kills the cancer cells in the bloodstream, not after they’re reached their metastatic destination. He suggests inhibiting MCT1 would be more effective around stage 3, when the melanoma cells are in the bloodstream and lymph nodes.
“Our prediction is that blocking MCT1 won’t have much activity against stage 4 melanoma, but if used as an adjuvant therapy in stage 3, it might decrease the percentage of patients who progress to stage 4,” Morrison told STAT.
It is also possible this research has implications for MCT1 blocking and AZD3965 beyond melanoma. Other types of cancers, including lung and pancreatic, also utilize MCT1 to collect lactate in the bloodstream.
