New pharmacological strategies for cutaneous malignant melanoma

Human cutaneous melanoma is an aggressive and chemotherapy resistant type of cancer. Although the development of new targeted therapies and immunologic agents has completely changed the treatment guidelines, one of the most important tasks for the future will be to overcome acquired resistance. In this thesis we investigated different pharmacological strategies against human melanoma cells. Particularly, we demonstrated the theranostic properties (i.e., the ability of imaging and pharmacological silencing activity) of a molecular beacon-oligodeoxynucleotide (MB) that targets survivin mRNA. This may represent an innovative approach for cancer diagnosis and treatment in melanoma patients because survivin is an inhibitor of apoptosis overexpressed in tumor cells and almost undetectable in human melanocytes. We also provide evidence of the pro-apoptotic effect and cell cycle arrest ability of AM251, a cannabinoid type 1 receptor antagonist/inverse agonist with an anticancer potency comparable to that observed for cisplatin. This compound may be a potential prototype for the development of promising diarylpyrazole derivatives to be evaluated in human cutaneous melanoma. Finally, we demonstrated that the cannabinoid type 1 receptor is markedly expressed in stem-like cells and not expressed in the BRAF-wild type parental cells. Otherwise, both primary BRAF-mutated melanoma cultures and their correspondent melanoma-initiating cells expressed high levels of this receptor subtype. These findings suggest a possible role of the endocannabinoid system in determining the phenotype of melanoma cells and their potential to cause central nervous system metastases.