Anti-angiogenic therapy in pediatric neuro-oncology

In order to grow, tissues require additional nutrients and oxygen as well as removal of waste products. Tumors achieve this by up-regulating angiogenic cytokines and/or down-regulating natural inhibitory proteins that allow neovascularization to proceed. Brain tumors continue to account for significant morbidity and mortality, in spite of significant advances in neurosurgical and radiation techniques and new chemotherapy combinations. As such, there is a real and immediate need for novel biologic therapies that can target these tumors. A number of new drugs that target different aspects of the angiogenic cascade have been identified and are now in clinical trials in children with primary brain tumors. In many of these pre-clinical and clinical studies, anti-angiogenic therapy has been well tolerated, has lacked many of the traditional toxicities of radiation and chemotherapy, does not require blood-brain barrier penetration, and targets a critical pathway in central nervous system tumor development. This review will discuss what angiogenesis is, how pediatric brain tumors regulate angiogenesis to obtain a vascular supply, what types of inhibitors are available, how different classes of inhibitors work, the types of resistance possible, how rapidly these inhibitors may work, and what surrogate markers of activity are available to follow response.