Nowadays, oncogene-directed therapy and immunotherapy represent the two most promising avenues for patients with metastatic melanoma. The recent oncogene-directed therapeutic, vemurafenib, usually produces high level of tumor shrinkage and survival benefits in many patients with B-RA mutant melanomas, although the fast and high degrees of responses are likely short-lived. Conversely, the newly-approved immunotherapeutic, ipilimumab, produces durable responses in patients presenting CTLA-4 T-cell surface protein. Nevertheless, the possible synergy in combining these two therapeutic strategies primarily rely on the rational design of medical protocols (e.g., sequence and timing of agent administration; drug selectivity; compatibility of combined therapies i.e., adoptive T cell or agents, i.e., MEK inhibitor trametinib, PD-1 and PDL-1 blockers). Improved therapeutic protocols shall overcome therapeutic limitations such as the (i) tolerability and safety (i.e., minimal toxic side-effects); (ii) progression free survival (e.g., reduced relapse disease frequency); (iii) duration response (i.e., decreased drug resistance). Eventually, multidisciplinary approaches are still requested (e.g., genomics for personalized medicine, nanomedicine to overcome low free-drug bioavailability and targeting, systematic search of “melanoma stem cells” to enhance the prognosis and develop more valuable theranostics). In this paper, I will mainly present and discuss the latest and promising treatments for advanced cutaneous melanomas. 1. Introduction Melanoma (from Greek—melas: “dark”) is a tumor originated from malignant transformation of melanocytes (i.e., melanin pigment-producing cells) that can be found in the skin, bowel, and eye [1]. According to the estimations provided by the American Cancer Society (ACS) in 2010, 68.130 new cases of melanomas were diagnosed and approximately 8.700 people died from this cancer [2]. The incidence of melanoma in the US has increased of about three folds between the last three decades (i.e., from 7.89 per 100.000 in 1975 to 22.52 per 100.000 in 2008) [3]. Clinical and epidemiological data suggest that several risk factors can contribute to the increased incidence: (i) extensive or repeated exposure to sunlight [4]; (ii) individuals with family history of melanoma (5–12% of all reported cases) [5]; (iii) high nevi count and dysplastic nevus [6], thereby suggesting the need to perform a biopsy of the suspicious lesion. The biopsy permits to establish not only an accurate diagnosis but also to define the optimal staging and proceed earlier
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