Anti-angiogenic Therapy in Pediatric Neuro-oncology

Abstract

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.

Phase II study of metronomic chemotherapy for recurrent malignant gliomas in adults

“…11,50 There are several studies using metronomic chemotherapy for a variety of cancers, including brain tumors. [51][52][53][54][55] An interim analysis of a phase II study of 16 adults with recurrent AGs using thalidomide and daily low-dose cyclophosphamide appeared promising, with three responses (one CR, two PR) reported. 56 The four-drug regimen used in this study was reported by Kieran et al 27 to be well tolerated in pediatric patients with recurrent malignancies.…”

Gene‐linked shift in ganglioside distribution influences growth and vascularity in a mouse astrocytoma

“…2001; Mukherjee et al . 2004; Kieran 2005), the shift in CT‐2A ganglioside distribution may reduce growth and vascularity through effects on the angiogenic properties of the microenvironment. For example, shed gangliosides from tumors in the ECM can either enhance or suppress angiogenic responses through autocrine and paracrine effects on tumor cells and tumor‐associated host cells (endothelial and macrophages) (Yohe et al .…”

Small molecule inhibitors in children with malignant gliomas

“…In order for a tumor to grow, it must expand its blood supply to provide the enlarging mass sufficient oxygen and nutrients to sustain growth. Neoplastic angiogenesis is achieved by up-regulating one or more of the 40 positive factors that turn on angiogenesis and/or down-regulating the natural inhibitors of this process [26]. The best characterized of the stimulators of angiogenesis include VEGF and basic Fibroblast Growth Factor (bFGF).…”

“…Incorporating stable disease into the assessment of the activity of this class of agents will make direct evaluation even more complicated. Small molecule inhibitors of certain pathways such as those targeting the angiogenic cascade may actually permit some initial tumor growth before stabilization and/or tumor regression is observed [26]. Since many tumors have already generated significant neovascularization, inhibitors will need first to stop the addition of new vessels and then begin to pare down those already present.…”

“…Small molecule inhibitors are usually orally administered, well tolerated, and their small size allows for better tumor site and CNS penetration. Those targeting the microenvironment, such as endothelial cells, are accessible directly from the blood and do not require any penetration to be effective [26,27].…”