Personalized Medicine in Malignant Melanoma: Towards Patient Tailored Treatment

Abstract

Despite enormous international efforts, skin melanoma is still a major clinical challenge. Melanoma takes a top place among the most common cancer types and it has one of the most rapidly increasing incidences in many countries around the world. Until recent years, there have been limited options for effective systemic treatment of disseminated melanoma. However, lately, we have experienced a rapid advancement in the understanding of the biology and molecular background of the disease. This has led to new molecular classifications and the development of more effective targeted therapies adapted to distinct melanoma subtypes. Not only are these treatments more effective but they can be rationally prescribed to the patients standing to benefit. As such, melanoma management has now become one of the most developed for personalized medicine. The aim of the present paper is to summarize the current knowledge on melanoma molecular classification, predictive markers, combination therapies, as well as emerging new treatments.

Keywords: functional selectivity; melanoma; receptor tyrosine kinases; signaling; targeted therapy; ubiquitination.

Figure 1

Receptor tyrosine kinases (RTKs) (IGF-1R) signaling network and points of therapeutic blockade. The canonical RTKs signaling can be represented as a system of three layers. The input layer (i) is made up of ligands (e.g., insulin, insulin-like growth factor 1, IGF-2) and surface receptors (IGF-1R, insulin receptor). Ligand–receptor interaction initiates activation of the second layer (ii) (the signaling cascade) through recruitment of the two main adaptor proteins; Shc and the IRS’s. Through stepwise enzymatic activation, the signal cascade is set up, following two main routes—the mitogen-activated protein kinase (MAPK) route and the phosphoinositide 3-kinase (PI3K) route. The signaling cascade arms culminate in the activation of transcription factors in layer (iii), which control site specific transcription and generate the resulting biological effects. The molecular changes associated to melanoma pathogeny and hence potential therapeutic targets are indicated within each of the system’s layers.