Cancer cannot grow or spread without new blood vessels that are produced in a process known as angiogenesis. This growth of blood vessels from the surrounding tissue to a solid tumor is caused by the release of chemicals by the tumor. These new blood vessels “feed” the tumor with oxygen and nutrients, stimulating it to grow and spread to nearby tissue and other parts of the body.
Research on animals has shown that the growth of melanoma and its ability to metastasize is dependent on the formation of new blood vessels. Anti-angiogenesis inhibitors are medicines that prevent new blood vessels from forming or extending and thus “starve” the cancer cells and ultimately inhibit cancer growth.
Several antiangiogenic agents have been and are currently being tested in patients with melanoma. In particular, anti-angiogenesis medications are also being explored in uveal melanoma. The list of tested agents includes:
- Bevacizumab (brand name Avastin) is the best known anti-angiogenic agent. It is a monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). In combination with chemotherapy it is approved for the treatment of patients with colon and lung cancer. It was tested in melanoma patients in combination with paclitaxel and carboplatin, but the treatment did not result in a significant improvement in overall survival. It has also been tested in combination with temozolomide, nab-paclitaxel ,and with nab-paclitaxel and carboplatin and has shown some activity. Currently this drug is being tested in combination with ipilimumab and vemurafenib.. In addition, there are attempts to increase the effectiveness of bevacizumab by adding everolimus or temsirolimus, inhibitors of a molecule called mTOR, which is also important for the growth of cancer cells and blood vessels.
- Axitinib is a novel oral multikinase inhibitor, targeting the vascular endothelial growth factor receptor (VEGFR). it has shown some activity, especially in patients with non-BRAF mutated melanoma. Further trials with this agent are ongoing.
- Pazopanib, a novel multikinase inhibitor of VEGFR-1,VEGFR-2, VEGFR-3, PDGFR-α and β, FGFR-1 and 3, and c-Kit., is being evaluated in combination with paclitaxel in advanced melanoma. It is currently FDA approved for treatment of renal cell carcinom.
- Lenvatinib is another oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT and PDGFRβ. It has shown some activity in earlyclinical trials in patients with non-BRAF mutated melanoma but with toxicities. It is also under investigation in patients with BRAF-mutated melanoma whose disease progressed after being treated with a BRAF inhibitor.
- Cabozantinib, a MET and VEGFR2 inhibitor, is being evaluated in clinical trials in both advanced cutaneous and uveal melanoma.
Other agents, such as thalidomide, lenalidomide, endostatin, sunitinib, and sorafenib, were also tested in melanoma with disappointing results.