Bcl-2 is an inhibitor of apoptosis that is overexpressed in approximately 80% of
melanoma cell lines and is believed to contribute to the development of resistance to cytotoxic
chemotherapy in patients with
melanoma.
Oblimersen, an
antisense oligonucleotide that stops the translation of Bcl-2
mRNA to
protein, significantly improved progression-free survival when administered in combination with
dacarbazine. Overall survival was significantly improved in patients with low levels of serum
lactate dehydrogenase (LDH), but not in patients with elevated LDH. RAF
proteins are a family of
serine/threonine kinases that regulate many aspects of cellular function. RAF mutations occur in 70% of
melanoma cell lines. Although
RAF kinases are thought to be important in the pathogenesis of
melanoma, RAF inhibition with
sorafenib has not significantly improved survival in patients with advanced disease.
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a naturally occurring inhibitor of T-cell function that prevents the complete activation of T cells upon exposure to
antigens by antigen-presenting cells. Two
monoclonal antibodies to CTLA-4 (
tremelimumab and
ipilimumab) have been developed to promote T-cell activation in
melanoma and other types of
cancer. Phase I and phase II clinical trials of these agents in patients with metastatic
melanoma have demonstrated promising effects on
tumor progression, with objective response rates of approximately 20% and sustained responses in some patients. Several
vaccines have been developed to stimulate immune system responses against
melanoma. Despite promising early findings with polyvalent
melanoma vaccine and with
vaccine containing
heat shock proteins, results with these agents in larger clinical trials have been disappointing.
CONCLUSION: