Scientists at the University of East Anglia (UEA) in Norwich, England recently published research indicating the combination therapy of the immunosuppressive drug lefflunomide when combined with Astra Zeneca's anticancer candidate selumetinib almost completely stopped the growth of a melanoma tumor when given to mouse study models. The findings could bode well for new treatments for melanoma which often becomes resistant to most available drugs treating the disease.
“By combining therapies, it's possible to attack the disease from several angles, which makes it harder for the melanoma to develop resistance to any of the drugs,” said Grant Wheeler, Ph.D., from UEA's School of Biological Sciences. “Our research has shown that there could also be further benefits. [By] joining these two drugs together you may be able to enhance their effects, getting a treatment that is more than the sum of its parts.”
Wheeler, along with colleagues from Norwich Medical School and UEA's School of Pharmacy, focused on leflunomide, an immunosuppressive drug approved for treatment of rheumatoid arthritis. Previous research by the team had shown it to be effective in use with drugs that target melanoma with a certain genetic mutation, known as BRAFV600E.
Their latest study (“The Anti-Rheumatic Drug, Leflunomide, Synergizes with MEK Inhibition to Suppress Melanoma Growth”), published in Oncotarget, provided more information about how leflunomide works against melanoma and tested it in combination with another melanoma drug, selumetinib, which targets the protein MEK that is activated in melanoma. Inhibiting MEK blocks cell proliferation and leads to apoptosis. MEK inhibitors are already used in combination with BRAF inhibitors to combat resistance, but Wheeler's research demonstrated that the addition of leflunomide may make it more effective.
“We have further characterized the function of leflunomide and show that the drug reduces the number of viable cells in both wild-type and BRAFV600E mutant melanoma cell lines. Further experiments have revealed leflunomide reduces cell proliferation and causes cells to arrest in G1 of the cell cycle. Cell death assays show leflunomide causes apoptosis at treatment concentrations of 25 and 50 μM. To determine if leflunomide could be used combinatorialy with other anti-melanoma drugs, it was tested in combination with the MEK inhibitor, selumetinib. This combination showed a synergistic effect in the cell lines tested. This drug combination led to an enhanced decrease in tumor size when tested in vivo compared to either drug alone, demonstrating its potential as a novel combinatorial therapy for melanoma,” wrote the investigators.
Questions remain to be answered before this combination could go into clinical trials, including testing whether melanoma can develop resistance to the treatment, noted Wheeler.
“With melanoma treatments, the main problem has been the development of tumor resistance. One way this is being combatted is through immunotherapy treatments that harness the body's own defenses. However, new combination therapies are always needed, and we need to identify new drugs that can be added to the arsenal of antimelanoma therapies available for patients. It's possible that leflunomide could play that role,” he said.
