Associação Portuguesa de Investigação em Cancro
Ipilimumab and Vemurafenib: Two promising therapies against melanoma
Ipilimumab and Vemurafenib: Two promising therapies against melanoma
Melanoma, a malignant tumor of melanocytes, causes the majority (75%) of all skin cancer-related deaths. The overall efficacy of different anti-cancer therapies on metastatic melanoma is quite limited, due to its high resistance to all forms of conventional treatments, including chemotherapy, radiotherapy and immunotherapy, leading to low patient survival rates. The present review identifies possible strategies for the treatment of advanced melanoma and describes two novel agents, Ipilimumab and Vemurafenib, which may now be useful for clinical practice. Ipilimumab, a humanized, IgG1 monoclonal antibody, acts through immune-modulation since it blocks cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), producing favourable antitumor immune system responses and reducing tolerance to tumor-associated antigens. Vemurafenib is a novel oral small-molecule kinase inhibitor with high selectivity and efficacy toward a specific mutated oncogenic BRAF-signalling mediator. The mechanism of action of Vemurafenib involves selective inhibition of the mutated BRAFV600E kinase that leads to reduced signalling through the aberrant MAPK pathway. However, as patients commonly develop Vemurafenib resistance, clinical trials of Vemurafenib in combination with Ipilimumab or other targeted or cytotoxic chemotherapeutic agents may provide more effective regimens with long-term clinical benefits, emphasizing the importance of simultaneously targeting several pathways. As both drugs had only modest effects on median survival, new therapeutic combinations are needed, such as BRAF inhibitors with MEK inhibitors or combinations of immunomodulators and pathway inhibitors. Such strategies should have the potential of maximizing antitumor effect while minimizing and improving clinical benefit. Nevertheless, these two new agents open a promising view into an effective management of melanoma.
Ana Burgeiro (1, 2), Faustino Mollinedo (3), Paulo J. Oliveira (1)
1 - CNC – Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
2 - BEB – PhD Programme in Experimental Biology and Biomedicine, University of Coimbra, Coimbra, Portugal.
3 - Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-Universidad de Salamanca, Campus Miguel de Unamuno, E-37007 Salamanca, Spain.
Melanoma is a malignant tumor of melanocytes, resulting in the majority (75%) of all skin cancer-related deaths. When melanoma spreads to distant tissues, it is generally considered incurable and the median survival is 6 to 12 months. Metastatic melanoma is very resistant to all forms of conventional therapies, such as chemotherapy, radiotherapy and immunotherapy, showing a notorious resistance to cytotoxic agents. So, novel effective agents or combined regimens are very welcome. Recently, two novel agents for the treatment of advanced melanoma, Ipilimumab and Vemurafenib, were described, both very useful for clinical practice. Ipilimumab produces favorable antitumor immune system responses and reduces tolerance to tumor-associated antigens. Vemurafenib is highly selective and efficient toward a specific mutated oncogenic BRAF-signaling mediator. Despite both drugs show only modest effects on median survival, new therapeutic combinations are on clinical trials, such as the combination of BRAF and MEK inhibitors or combinations of immunomodulators and pathway inhibitors. Such strategies may have the potential of maximizing antitumor effect and improving clinical benefit. Nevertheless, these two new agents open a promising view into an effective management of melanoma.
Current Cancer Drug Targets
http://www.ncbi.nlm.nih.gov/pubmed/23862981
