In the past few years, we have seen unprecedented gains in the treatment of metastatic melanoma. This disease in its advanced stages has always had a dire prognosis, with patients on average surviving a matter of months. But we have entered an era when cures are increasingly occurring, with some patients living 5-10 years and counting.
“Targeted therapy” has been the springboard for this revolution, often replacing chemotherapy’s scattershot attack on both diseased and healthy cells or relegating it to a complementary role. By gaining insights into the molecular drivers of cell division, senescence, and apoptosis, and unraveling many of the immune system’s complex interactions with cancer cells, scientists have been able to develop strategies specifically inhibiting not only defective genes that switch on melanomas, but also certain brakes on the immune system that stop T-cells from attacking. These new therapies offer hope to patients who once had little.
Still, only 16 percent of patients with distant metastases attain 5-year survival, and much remains to be learned about how best to employ these new therapies: when and how to use them, how to choose among them, and whether to use them alone, in combination, or sequentially to minimize toxicities and circumvent drug resistance. In our lead story, Drs. Momtaz, Lacouture, and Chapman explore in detail just how far we’ve come in this targeted revolution, and how much further we have to go.
The BRAF inhibitor vemurafenib is an object lesson in how complex the process of discovery will be. The first drug approved to block signaling along the mitogen-activated protein kinase (MAPK) pathway driving melanoma cells, it has provided at once some of the greatest thrills and greatest disappointments of the targeted era. As Chapman and coauthors point out, in mutant-BRAF-hyperactivated cells, vemurafenib immediately shuts down the MAPK pathway, leading to rapid reductions in metastatic tumor volume that can restore patients’ mobility, functionality, and wellbeing. Initially, based on these breathtaking results, many were naïvely optimistic that the MAP-kinase pathway would prove easy to manipulate and that simply blocking the BRAF molecule, mutated in about 50 percent of melanomas, would result in cell cycle arrest and cure. However, despite some durable responses, the development of drug resistance has proven to be the norm rather than the exception. We have come to realize that the MAP-kinase pathway is in fact extremely intricate and will take much more manipulation before we solve the problem of drug resistance.
Some researchers speculate that BRAF-mutated melanomas harbor a subpopulation of malignant cells that grow more efficiently with BRAF inhibition, essentially becoming addicted to the drug itself and being nourished by it. In other words, when BRAF inhibition stops the growth of BRAF-sensitive malignant cells, it may selectively enhance the growth of resistant cells, ultimately defeating the therapy. Researchers are now seeking to create a balance between the BRAF-sensitive and resistant cell populations so that neither grows out of control, creating a homeostasis that might prove lifesaving. In our fascinating second story, Dr. Martin McMahon and Marian Deuker discuss their research into intermittent dosing with BRAF inhibitors as one means of creating such a homeostasis.
Recent advances in melanoma therapy after decades of disappointment have prompted optimism, if not impatience, for a cure. Unfortunately, many hurdles remain and the road to further breakthroughs may be long. But with researchers working out the intricacies of how best to shut down defective pathways and harness the immune system, there is indeed much reason for hope that each new discovery will help more patients to live longer and better.
Allan C. Halpern, MD
Ashfaq A. Marghoob, MD