Somatic genetics and targeted therapies for cutaneous melanoma

Abstract

The standard treatments for metastatic melanoma have not evolved in the past 30 years. It has been a decade since the emergence of high-dose interferon in the adjuvant setting: a therapy with significant limitations in both efficacy and tolerability. The conventional therapies that have proven useful for other cancers have been exhausted with regard to their exploration in melanoma and novel approaches are required. The identification of somatic genetic alterations that activate the MAP kinase and PI3 kinase pathways has provided a foothold for the investigation of signal transduction inhibitors that counter them. Melanoma is more complex than some of the cancers with early success in the application of signal transduction inhibitors, such as chronic phase chronic myelogenous leukemia or gastrointestinal stromal tumors, with regard to the number of genetic aberrations found within any one cell. While reductive laboratory studies have supported the potential therapeutic value of inhibitors of these and other signaling pathways in melanoma, even those experiments do not suggest that every cell in a given tumor will be eradicated with agents that target a single pathway. The current generation of clinical trials, which seek to develop novel signal transduction inhibitors, will ultimately provide the building blocks for regimens that take into account the greater complexity of melanoma at the level of aberrant signal transduction.