The successful treatment of
melanoma has been hampered by the unique biology of this
cancer. Fortunately, research to further our understanding of how
melanoma cells differ from normal tissues has led to the discovery of potential new avenues of attack. One promising strategy relates to targeting the excess
free radicals produced by
melanomas. Melanocyte transformation into
cancer is associated with significant structural alterations in the melanosome. In addition to pigment production, melanosomes also protect the cell by scavenging
free radicals generated by sunlight and cellular metabolism. In
melanoma, the disrupted and disorganized melanosome structure reverses this process. Melanosomes found in
melanoma produce
free radicals, such as
hydrogen peroxide, furthering DNA damage. Melanosome generation of
reactive oxygen species (ROS), in tandem with those generated by
cancer metabolism, activate cellular signal transduction pathways that prevent cell death. ROS activation of proto-oncogene pathways in
melanoma contributes to their resistance to
chemotherapy. Fortunately, it may be possible to target these
free radicals, just as Paris was able to successfully target Achilles' heel. The use of agents that block ROS scavenging, such as
ATN-224 and
disulfiram, have been explored clinically. A recent randomized Phase II trial with
elesclomol, an agent that generates ROS, in combination with
paclitaxel led to improved patient survival, suggesting that this may be a viable approach to advance the treatment of
melanoma.