More than one-third of melanomas are ‘pan-negative,’ meaning they lack known mutations that can be targeted for treatment. But now researchers have identified two new genetic abnormalities in pan-negative melanomas. These abnormalities consist of the BRAF gene joined with another gene (PAPSS1 or TRIM24), and so are called BRAF fusions. The new study showed that about 8% of pan-negative melanomas have BRAF fusions. Next, the researchers grew melanoma cells with these BRAF fusions in the lab and tested known targeted treatments on them. While these cultured cells were not sensitive to the BRAF inhibitor vemurafenib, they were sensitive to the MEK inhibitor trametinib, suggesting that MEK inhibitors could be used to target melanomas with these BRAF fusions.
New research shows that melanoma is more likely to strike twice in people with melanomas that have spread. The researchers studied 7,800 people with advanced melanoma who had not been treated with drugs, known as BRAF inhibitors, and found that new skin melanomas arose in 5% of those with stage III melanoma (229 out of 4,215) and in 1% of those with stage IV melanoma (43 out of 3,563). New skin melanomas were more common in men as well as in people who had previously had more than one skin melanoma. The researchers note that people treated with BRAF inhibitors have even higher rates of new skin melanomas, but caution that they also get more skin checks.
Because melanomas can quickly resist BRAF inhibitor drugs alone or in combination with MEK inhibitors, researchers are testing a new combination treatment: the BRAF inhibitor vemurafenib and PX-866, which inhibits a cancer pathway called PI3K. In a phase I/II clinical trial of 19 people with melanomas that have BRAF mutations, the vemurafenib/PX-866 combination shrank tumors in 10 of them. These findings were presented at the 10th International Congress of the Society for Melanoma Research in Philadelphia. However, while results so far are encouraging, it will take larger trials to see if this new combo treatment really overcomes drug resistance in melanomas. This ongoing trial is still accepting new participants.
We already knew that melanomas can resist BRAF inhibitor drugs by activating a particular cancer pathway (a group of proteins in a cell that work together to control cell multiplication, which can lead to tumor growth)—but new research shows that this resistance can also be caused by activating a second cancer pathway. The first pathway is called MAPK and the second is called PI3K-PTEN-AKT. The researchers studied 100 melanomas that resisted the BRAF inhibitors vemurafenib or dabrafenib, and found that 70% had mutations in the first pathway, while 22% had mutations in the second pathway. Moreover, mutations in both pathways could occur in the same tumor, suggesting that thwarting resistance to BRAF inhibitors may require targeting both pathways with a combination treatment.
Two targeted treatments that are U.S. Food and Drug Administration (FDA)-approved for melanoma may be even more effective together. The drugs are dabrafenib, a BRAF inhibitor, and trametinib, a MEK inhibitor. In a phase II clinical trial with 160 people, the median survival was nearly 2 years with the combination treatment compared to 20 months with dabrafenib alone. These findings were presented at the 10th International Congress of the Society for Melanoma Research in Philadelphia, Pennsylvania. Now, the dabrafenib/trametinib combo has advanced to phase III trials.
Blocking a protein that protects tumor cells may shrink melanomas, according to results from an ongoing trial that were presented at the 10th International Congress of the Society for Melanoma Research in Philadelphia, Pennsylvania. Called PD-L1, the protein shields tumor cells from the immune system and it can be blocked by a drug called MPDL3280A. The phase I trial included 45 people with melanoma who were treated with the PD-L1 blocker, and tumors shrank in one-third of them. This PD-L1 blocker is also being tested in a phase I trial in combination with the BRAF inhibitor drug vemurafenib, as well as in several phase II trials against renal cell carcinoma and non-small-cell lung cancer (NSCLC). In addition, two drugs similar to this PD-L1 blocker (nivolumab and MK-3475) are being tested in phase III trials against melanoma.
“Inhibitors of BRAF protein kinase, such as Vemurafenib and Dabrafenib, have shown remarkable antitumor activity in patients with BRAF mutant melanoma. However, most of the patients developed drug resistance during the course of treatment, leading to resumed tumor growth. This drug resistance challenge underscores the need to improve on current BRAF-targeted therapy. In this study, we have shown that phenformin, a biguanide used for treating type 2 diabetes, enhances the antitumor activities of BRAF inhibitors in both cultured melanoma cells and a genetically engineered BRAFV600E-driven mouse model of melanoma. Our preclinical findings suggest that combining phenformin with a BRAF inhibitor may be a more effective treatment than a single-agent BRAF inhibitor for treating patients with melanoma whose tumor harbor BRAF mutations.”
Even though about half of melanomas have BRAF mutations, some of these still fail to respond to BRAF inhibitors. Now, there may be a way to tell whether BRAF inhibitors are working, according to findings presented at the 2013 International Conference on Molecular Targets and Cancer Therapeutics. The researchers found that a BRAF inhibitor kept tumors from growing in six out of nine people with BRAF-mutant melanomas, and that those who benefitted from the treatment also had less activation of a protein called S6 at two weeks. If this link is verified in large clinical trials, S6 activation levels could predict BRAF inhibitor effectiveness during the early stages of treatment.