Mechanisms and analysis of the CNS distribution of cediranib, a molecularly-targeted anti-angiogenic agent.

Abstract

The role of vascular endothelial growth factor (VEGF) in brain tumor angiogenesis via stimulation of its receptor (VEGFR) is well established, indicating that the tumor endothelium may be a potential target for brain tumor treatment. However, the current angiogenesis inhibitors used in clinical trials so far have shown limited effects on tumor growth and improvement in survival. Cediranib is an orally available small-molecule kinase inhibitor of all three VEGFR isoforms, with additional activity against PDGFRß and c-KIT. Its broad activities against critical targets, especially the anti-angiogenic activity, make cediranib an attractive option for therapy in central nervous system (CNS) tumors. Cediranib has shown promising anti-angiogenic efficacy in early clinical trials in glioblastoma (GBM), but its anti-tumor mechanisms and its effect on the efficacy of concurrent chemotherapies remain unclear. ATP-binding cassette transporters p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) have been shown to work in concert to restrict brain penetration of several tyrosine kinase inhibitors. This study investigated the influence of P-gp and BCRP at the blood-brain barrier (BBB) on the CNS penetration of cediranib. Although in vitro studies suggest that both P-gp and BCRP significantly affect intracellular delivery of cediranib, in vivo data indicated that P-gp is a dominant efflux transporter for cediranib and BCRP plays a minor role in limiting transport of cediranib across the BBB. The interaction of cediranib with these brain efflux transporters could limit the antiangiogenic and anti-tumor action in cells in the brain parenchyma and might lead to poor iv outcomes in clinical trials. A more thorough understanding of the mechanisms controlling the delivery of cediranib to its targets will allow more efficacious use of this drug in GBM. To better understand the brain distributional kinetics, simulation strategies were employed to explore the appropriate ways to compare the true brain partitioning among different transporter deficient transgenic mouse groups, which, in general, helps in exploring the contribution of each drug transporter to the brain drug delivery. There are two partial-areas analyses utilized to determine the exit rate constant from the brain, the performances of which were evaluated and compared in the current study. The requirement for accurate determination of the brain-to-plasma ratio of the area under the concentration-time curve (AUC) also warrants the investigation of a Bayesian approach to estimate the variability around the ∞ o AUC and the tissue-to-plasma ∞ o AUC ratio obtained by destructive sampling Since anti-angiogenic agents are commonly used in combination therapy for GBM, the influence of anti-angiogenic therapy on tumor delivery of traditional chemotherapy and molecularly-targeted agents was examined using a xenograft GBM model. It has been shown that restoration of the BBB integrity by cediranib and bevacizumab could decrease the tumor site delivery of both temozolomide and erlotinib, and even the delivery of cediranib itself, which could also be one of the reasons for the limited efficacy of cediranib in clinical trials.