Molecularly targeted therapy

Melanoma resistance to conventional medical treatments (i.e. radiotherapy and chemotherapy, see Conventional Therapy section) explains the virtual absence of therapeutic options in case of metastatic disease; furthermore, in the adjuvant setting melanoma refractoriness to antineoplastic agents has left clinicians with a single and still controversial therapeutic weapon, that is IFN-alpha. Therefore, the best current therapeutic approach for melanoma is early diagnosis. In the light of these considerations, novel anti-melanoma therapeutic strategies are urgently needed to give new hope to patients affected with this deadly type of cancer.

Most conventional antineoplastic approaches/agents (i.e. chemotherapeutic drugs and radiotherapy) are not tumor-specific and exert their cytotoxic effect mainly on proliferating cells, often relying on small differences in drug sensitivity between tumor cells and normal tissues to deliver a therapeutic benefit. Consequently, they have significant limiting toxicities (narrow therapeutic window/low therapeutic index, i.e. the odds for suffering from treatment-related adverse effects are similar or even superior to the probability of obtaining a clinical benefit) and greatly reduced efficacy against non-proliferating (dormant) or slowly growing (low-mitotic index) malignant cells (which are believed to be responsible for disease recurrence after apparently curative surgery or - much less often - apparently complete response to medical therapy).

Anticancer drug discovery is shifting from an empiric random screening approach to a more rational and mechanistic, target-directed approach, where specific abnormalities in cell functioning are modulated in a classical drug-receptor fashion [1]. Drugs targeting tumor specific pathways can be not only more effective but also less toxic. Recent clinical trials (including many randomized controlled trials, RCT) have demonstrated the therapeutic potential of such molecularly targeted agents against some tumors such as breast, colorectal, lung and renal cell carcinomas, chronic myeloid leukemia, and gastrointestinal stromal tumors (GIST) [2, 3].

Molecularly targeted anticancer therapy is based upon two main approaches, which should not be considered separately but rather in combination, with the aim to capitalize on their synergistic therapeutic effect :

This therapy-oriented molecular approach to cancer medicine requires a tight cooperation and intense exchange of knowledge between clinicians and basic researchers, a concept that has been recently developed and has reached the autonomous dignity of a discipline, called "translational medicine" [4].

Although targeted therapy is at an earlier stage of clinical implementation in the case of melanoma, the (still partial) elucidation of the cascade of molecular events underlying melanoma development and progression is fostering the interest of investigators in this field [5-14].