Targeting angiogenesis for the treatment of advanced melanoma

Abstract

Metastatic melanoma (MM) carries a dismal prognosis, as it is largely resistant to conventional chemotherapy, bio-chemotherapy and immunotherapy. The search for new effective treatments is an unquestionable priority in MM. A wealth of novel therapies have been currently tested in oncology and MM represents an attractive model for investigation. The process of angiogenesis is crucial for the establishment and progression of most solid tumors including melanoma. As the mechanisms of angiogenesis are being elucidated, strategies against angiogenic targets are among the most innovative in oncology drug development. Multiple growth factors secreted in melanoma trigger angiogenic responses and a variety of receptors are activated. Many of these function in synergy with the extracellular matrix, setting in motion downstream pathways. It is unlikely, therefore, that targeting a single angiogenic axis will be sufficient to achieve tumor control in melanoma, as exemplified by several negative trials conducted to date. Current anti-angiogenic strategies include those targeting pro-angiogenic ligands (bevacizumab, VEGF-Trap: aflibercept), kinases associated with cell surface receptors and growth factor pathways (sorafenib, axitinib, erlotinib, imatinib), matrix metalloproteinases (MMPs), intergrins [batimastat, marimastat, etaracizomab (abegrin)] and potentially mTOR inhibitors (everolimus). Many of those recently developed compounds targeting key angiogenic pathways are in the final clinical trial stages. Future approaches to tackling angiogenesis in MM should take into account therapeutic synergism and drug resistance, by combining novel agents with different mechanisms of action against different angiogenic pathways. In this review, we focus primarily on current anti-angiogenic strategies in melanoma, with a view to future developments.