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Scientists find potential drug targets for hard-to-treat melanoma

November 16, 2014

Female with Melanoma

As gene sequencing technologies became increasingly advanced, scientists learned that individual cancers, even when they were from the same type of malignancy, were much less homogeneous than previously believed. This has opened the door to personalized medicine, in which patients are treated based on their own genetic profiles rather than as parts of larger population groups. In some cases, however, simply looking at individual genes has not provided enough answers but new approaches to gene sequencing that look at fusions between genes may broaden researchers' scope of solutions.

For example, one team of scientists from the Vanderbilt-Ingram Cancer Center in Nashville, Tennessee, demonstrated how targeted next-generation sequencing revealed gene fusions that drive hard-to-treat melanoma, as published in the journal Clinical Cancer Research.

"About 35 percent of melanomas are, as of today, considered 'pan-negative,' which means they are devoid of any previously known driver mutations in the genes BRAF, NRAS, KIT, GNAQ and GNA11," Jeffrey Sosman, M.D., professor of medicine at Vanderbilt-Ingram Cancer Center and a Stand Up To Cancer Melanoma Dream Team investigator, said in a statement. "Here at Vanderbilt, we have been interested in looking at patients whose tumors have none of these driver mutations, to see what their tumors do have that can be targeted therapeutically."

'Pan-negative' may not be truly 'pan-negative'
According to the National Cancer Institute, about 76,000 new cases of melanoma will be diagnosed in the U.S. by the end of 2014. During the same time period, more than 9,700 people will die from the disease. Although melanoma makes up less than 5 percent of cases of skin cancer, it accounts for the most deaths.

Given that pan-negative melanoma had provided researchers and doctors no therapeutic targets, the authors of the new study expanded the scope of their search. Specifically, they used targeted next-generation gene sequencing to look for abnormal fusions between relevant genes. Previously, they had found one PAPSS1-BRAF fusion in a patient sample, prompting a hunt for more. This experiment involved 51 melanoma patients, 24 of whom were pan-negative. Ultimately, the researchers found one other fusion between a patient's BRAF and TRIM24 genes.

Laboratory analyses revealed that both BRAF fusions activated the MAPK signaling pathway. They then studied the effects of a BRAF inhibitor and a MEK inhibitor, the latter of which suppresses the MAPK pathway, on cancer cells that had BRAF fusions. They discovered that the MEK inhibitor was more effective in stopping the cancer cells.

These results are important because though the mutations are novel findings, they are responsive to medications that have already been approved by the U.S. Food and Drug Administration. Such a finding may not have been possible without the help of targeted next-generation sequencing methods.

Ultimately, the research underscores the possibility that researchers who are trying to promote personalized medicine need to look beyond singular genes and explore the occurrence of other aberrations, including gene fusion.