Molecular Mechanisms and Clinical Implications in Melanoma Brain Metastasis: New Insights

Abstract

AIM: Metastatic spread of melanoma to the brain is a common and devastating manifestation of disease progression. Understanding the various molecular events is critical to develop new therapies for melanoma brain metastasis. METHODS: The literature-based review was conducted by searching for keywords in Pubmed using the search terms: ‘melanoma’, ‘metastatic melanoma’, ‘brain metastasis’, ‘molecular basis’, ‘immunotherapy’ and ‘targeted therapy’. RESULTS: The molecular mechanisms implicated in melanoma brain metastasis include signaling pathways, proteases and surface markers involved in the formation of brain metastases. Dabrafenib (specific inhibitor of mutated BRAFV600E protein) may be more effective than vemurafenib (mutant BRAF inhibitor) for patients with advanced melanoma with brain metastases. CONCLUSIONS: Since the central nervous system (CNS) lacks a lymphatic system, tumor cells can only reach the brain parenchyma by hematogenous metastasis formation. During this process metastatic cells need to traverse brain endothelial cells which in turn form the morphological basis of the blood-brain barrier (BBB). The most important cellular elements of the BBB are endothelial cells, astrocytes and pericytes. Targeted therapies are highly recommended to be incorporated into the multimodality management of melanoma brain metastasis. Nanoparticles have been studied extensively for drug delivery, to increase anticancer treatment efficacy. Drugs delivered by nanoparticles may have a longer biological life, due to packaging protection, and may be concentrated in the site of cancer due to enhanced permeability and retention (EPR) at cancer sites. Nanoparticles produce a constant release of delivered drugs. Nanoencapsulation of the recent FDA-approved drugs might be beneficial.