Researchers working at frontiers of melanoma research

At Moffitt Cancer Center, patients with stage III and IV unresectable melanoma are now routinely genetically profiled for several gene mutations, including the BRAF gene, a known driver oncogene for melanoma. Research has shown that mutations in the BRAF gene determine sensitivity or resistance to a class of drugs that are BRAF inhibitors. "We have found that a large number of patients with melanoma who have the BRAF gene mutation quickly develop resistance to drugs that are BRAF inhibitors," said Jeffrey S. Weber, M.D., Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt. "A recent approach in the melanoma research community is to find ways to overcome resistance to drugs we targeted to mutated BRAF." At Moffitt, researchers have access to a large database of patient-donated tissues through Moffitt's Total Cancer Care™ program, a far-reaching design for care that includes building a biorepository of tumor samples for study and patient selection for clinical trials participation. By looking for patient genetic profiles for BRAF, Moffitt researchers are working at the frontiers of personalized medicine, which is the effort to match the right patient to the right drug. According to Weber, although 50 percent of melanoma patients might have the BRAF mutation, the lack of other valid molecular targets for melanoma has "hampered efforts to individualize therapy." That may have changed now that the U.S. Food and Drug Administration approved the drug Vemurafenib for melanoma patients who test positive for the BRAF mutation. An international team of researchers, including those at Moffitt led by Weber, found that when tested in a phase II clinical trial, Vemurafenib was highly effective for patients with previously treated metastatic melanoma that had the BRAF mutation. The study was published in a recent issue of The New England Journal of Medicine (366;8). However, Moffitt researchers know that patients can develop resistance to Vemurafenib and, consequently tested six different models of Vemurafenib resistance against an "inhibitor" called XL888. Their findings appeared in a recent issue of Clinical Cancer Research, a publication of the American Association for Cancer Research. "We found that the inhibitor XL888 overcomes Vemurafenib resistance through a number of mechanisms," said Keiran S. Smalley, Ph.D., of Moffitt' s Departments of Molecular Oncology and Cutaneous Oncology and who is a colleague of Weber and the senior author on the study. According to Smalley, there was already evidence that one of a family of inhibitors called HSP90 could overcome multiple drug chemotherapy resistance mechanisms in a number of cancers, including non-small cell lung cancer and breast cancer. They hoped it would help arrest the cancer cell cycle in melanoma cell lines resistant to the BRAF inhibitors. "Responses to XL888 were highly durable, with no resistant colonies emerging after four weeks of treatment," Smalley said. "In control studies not using XL888, resistant colonies emerged in every case." For Weber, the success of Vemurafenib represents "the single most dramatic improvement in the treatment of melanoma in 20 years." "The 53 percent response rate on the Vemurafenib study for previously treated melanoma patients with the BRAF mutation was significantly better than response rates seen in studies of other therapies for melanoma," Weber said. "To be able to find a mutation through gene profiling and develop a test to match a patient to the best treatment for them is the kind of personalized medicine we want to be known for at Moffitt."