January 1, 2014
Newly Discovered Molecular Targets May Treat Difficult Melanomas
redOrbit Staff & Wire Reports - Your Universe Online
A recently-published study in the journal Clinical Cancer Research supported by the Stand Up To Cancer (SU2C) charitable foundation has identified new molecular targets which could potentially result in new remedies for difficult-to-treat melanomas.A team of investigators, including Dr. Jeffrey A. Sosman of the Vanderbilt-Ingram Cancer Center and Dr. William Pao of the Vanderbilt University School of Medicine, found two novel BRAF fusions in skin cancers previously believed to lack molecular targets. Furthermore, they found that melanomas with these fusions might be sensitive to anticancer drugs known as MEK inhibitors.
BRAF genes provide instructions for the creation of a protein that transmits chemical signals from the outside of a cell to its nucleus. It is part of a class of genes known as oncogenes, and if these genes mutate they can cause cells to become cancerous, the US National Library of Medicine explained.
According to Dr. Sosman, approximately 35 percent of all melanomas are currently considered “pan-negative,” meaning that they lack any previously known driver mutations in the BRAF gene or other potential genetic triggers (including mutations in the NRAS, KIT, GNAQ, and GNA11 genes).
He said that he and his colleagues have been studying patients lacking these driver mutations, searching for potential treatment targets within their tumors. In some forms of cancer, two or more genes fuse erroneously, producing irregular proteins that can effectively serve as the “drivers” of their cancers.
“Performing a sophisticated analysis called targeted next-generation sequencing, it appears that about 8 percent of pan-negative melanomas have BRAF fusions,” Dr. Sosman explained in a statement. “Our results are important because they obviously suggest that there probably are other, as yet unidentified, molecular changes that make these melanomas susceptible to drugs that are available right now.”
Dr. Sosman and Dr. Pao analyzed a pan-negative melanoma sample from one of their patients, and found a fusion between two genes (PAPSS1 and BRAF) which they dubbed PAPSS1-BRAF. They then went on to study melanomas from 51 other patients, including 24 which were pan-negative. In those two-dozen pan-negative samples, they found a second novel BRAF fusion, which they called TRIM24-BRAF.
Following additional research, the doctors and their colleagues found that both of these newly-discovered BRAF fusions activated a pathway in the cancer cells known as the MAPK signaling pathway. They treated these cells with either a BRAF inhibitor (vemurafenib) or an MEK inhibitor (trametinib).
Vemurafenib proved ineffective, but the study authors found that BRAF fusions could be inhibited by trametinib. This led Dr. Sosman and Dr. Pao to suggest that the newly-identified novel fusions could cause the melanoma cells harboring them to become sensitive to this drug and other MEK inhibitors.
"One of the primary objectives of Stand Up To Cancer is to accelerate the development of effective treatments to help patients,” said SU2C Scientific Advisory Committee member Dr. William G. Nelson. “This research from Drs. Sosman and Pao advances that objective because identifying novel genetic mutations helps identify targets that might be sensitive to existing or future drug therapies.”