Prospects for therapeutic inhibition of neuroblastoma angiogenesis.
Despite aggressive therapy, survival for advanced stage neuroblastoma remains poor with significant long-term morbidity in disease survivors. High-risk disease features are strongly correlated with tumor vascularity, suggesting that angiogenesis inhibitors may be a useful addition to current therapeutic strategies. However, challenges include the well-known clinical heterogeneity and embryonal origins of this disease, which suggests a complex regulation of neovascularization that may be distinct from epithelial-derived carcinomas. We will review what is understood about angiogenesis-related signaling in neuroblastoma. In particular, we will present evidence that angiogenesis-related molecules are differentially expressed in primary neuroblastomas in a pattern suggesting promotion of a pro-angiogenic phenotype in high-risk tumors and an anti-angiogenic phenotype in low-risk tumors. We will also discuss a variety of vascular inhibition strategies that have been used in neuroblastoma preclinical models including specific inhibition of vascular endothelial growth factor (VEGF) and methionine aminopeptidase 2 (MetAP2). Recent observations that the combination of angiogenesis inhibitors with conventional chemotherapy provides synergy without additive toxicity, suggests the potential use of angiogenesis inhibitors as an adjunct between cycles of conventional cytotoxic therapy. Further identification of critical angiogenic signaling pathways and evaluation of specific inhibitors in preclinical neuroblastoma models should provide justification for future selection and evaluation of angiogenesis inhibitors in clinical trials for high-risk neuroblastoma patients.