Melanoma is an aggressive form of skin cancer that begins in the pigment-forming cells of the skin called melanocytes. While melanoma accounts for less than 5 percent of all skin cancers, it is far more serious than other skin cancers if not detected and treated early, before it has a chance to metastasize, or spread, to nearby lymph nodes and organs. Once the cancer has spread, the chances of achieving treatment success drop significantly. Recently, preliminary findings from a study led by Memorial Sloan-Kettering investigators have revealed rapid and dramatic shrinking of metastatic tumors in patients treated with a new compound that interrupts a tumor-growth pathway present in the majority of patients with melanoma.
Turning Melanoma "On" and "Off"
Mutations in the BRAF gene are present in approximately 50 to 60 percent of patients with melanoma, and in a minority of patients with colon, breast, and lung cancers. Mutant BRAF proteins play a central role in the growth and survival of cancer cells -- "turning on" a metabolic pathway known as MAPK, which in turn leads to tumor growth. Since 2004, Memorial Sloan-Kettering researchers have been testing new drugs designed to turn off this pathway, with the aim of stopping melanoma from growing.
Memorial Sloan-Kettering investigators and colleagues from five other institutions -- University of Pennsylvania, Vanderbilt University, University of California, Los Angeles, M.D. Anderson Cancer Center, and Peter MacCallum Cancer Center, in Melbourne, Australia -- have conducted a phase I trial of the BRAF-inhibitor drug PLX4032. Unlike standard chemotherapy, which attacks the machinery involved in cell division, PLX4032 targets the underlying genetic program that is believed to be causing the uncontrolled cell growth by targeting mutant BRAF proteins.
In preliminary results from metastatic melanoma patients with the BRAF mutation, 19 of the 27 patients who have been evaluated so far had their tumors shrink by a minimum of 30 percent taking 960mg of PLX4032 by mouth two times a day.
"Of the 27 patients we have been able to evaluate so far, almost all have had some objective tumor shrinkage, and 70 percent qualified as a true partial or complete response," says Paul Chapman, MD, one of the leaders of the trial and a medical oncologist specializing in the treatment of melanoma at Memorial Sloan-Kettering. "This is particularly impressive because they all had metastatic disease and most of them had failed prior therapies."
