ABOUT 50-TO-60 PERCENT OF PATIENTS WITH MELANOMA have a mutation in the BRAF gene that drives the growth of their cancer. In clinical trials, most of these patients have responded well to novel agents that inhibit the gene. Unfortunately, the response is almost always limited in duration, as the cancer develops resistance to the drugs.
In a study published in Cancer Research, scientists at UCLA’s Jonsson Comprehensive Cancer Center tested a combination of small molecules that, when used with the BRAF inhibitors, may help overcome the drug resistance and extend the lives of those with advanced melanoma.
The team, led by researcher Roger Lo, M.D., Ph.D., focused on testing only small molecules already being studied in various phases of clinical trials in the hope of developing a combination treatment that can be studied in patients much more quickly than compounds that aren’t yet being tested in humans. “The idea was to combine some of these molecules with the BRAF inhibitors and come up with something that we don’t have to wait years and years to use in patients,” Dr. Lo says. “We need to find a way to combine these molecules so the cancer cell cannot get around them.”
Cancer operates like a criminal seeking to evade his captors, and the small-molecule inhibitors act as police barricades that seek to block the criminal’s escape. When one of the cell-signaling pathways is blocked, the cancer finds a way to activate another pathway that will drive its growth. The goal is to find a way to block all the pathways helping the cancer evade therapy, so the cancer cells die before finding a way around the drugs.
In the lab, Dr. Lo and his team applied one drug at a time to the resistant cancer cells to see what route or pathway the cancer used to escape. They would then find an inhibitor for that pathway. In the end, the researchers identified the most optimal combination of molecules to block the pathways PI3K, mTORC and MEK.
“Normal cells have physiologic safety mechanisms to avert death, and this is taken to a higher level by the cancer cell to serve its growth agenda, making singleagent targeted therapy insufficient,” Dr. Lo says. “We have to block several roads, which is what is behind our approach to developing combination therapies. The key is to figure out how to combine the molecules, so that the cancer cannot get around them. Why wait for the cancer to escape? Let’s block all the pathways right from the start.”