Abstract 1023: Comparison of the effects of aflibercept (VEGF Trap) and small molecule kinase inhibitors on tumors and normal organs in mouse models
Authors: Ioffe Ella , Burova Elena , Nandor Sarah , Bai Yu , Rudge John S. , Thurston Gavin 
Published: August 2012

Abstract
Introduction: The VEGF signaling pathway is important for tumor angiogenesis, thus a number of approaches have been developed to therapeutically inhibit the pathway. Clinical benefit has been shown by both protein therapeutics that block VEGF itself, and by small molecules that target the kinase activity of VEGF receptors. However, it is not known whether these different classes of agents provide similar levels of VEGF inhibition in tumors, nor whether they produce a similar degree of perturbation to normal organs. In this study, we compared the effects of aflibercept (VEGF Trap), a protein inhibitor of VEGF, to those of the kinase inhibitors sorafenib and sunitinib on tumors and several normal organs in mouse models. Methods: Transcriptional profiles were compared from A431 human epidermoid carcinoma xenografts, as well as kidney, liver, lung and heart, following three days of treatment of mice with aflibercept (25 mg/kg, once), sunitinib (80 mg/kg, daily), or sorafenib (160 mg/kg, daily). All three agents were used at pharmacologically active doses that induce significant tumor growth inhibition. Kinase inhibitors were used at maximum dose that did not cause general toxicity such as body weight loss. RNA microarray was used to establish gene signatures, and real-time PCR was used to validate gene-specific expression levels. Results: Treatment of mice with sorafenib or sunitinib induced large-scale transcriptional changes in normal organs, including a significant overlap of the regulated genes and strong suppression of hemoglobin genes Hba and Hbb. In contrast, aflibercept treatment induced transcriptional changes in a much smaller number of genes in normal organs and had no significant effect on hemoglobin transcript levels. None of the agents changed expression of endothelial cell marker genes such as Pecam1 and Robo4 in these normal organs, indicating that VEGF inhibitors do not target stable vasculature. In tumor xenografts, aflibercept regulated a significantly larger number of stromal genes compared to either kinase inhibitor. Aflibercept, sorafenib or sunitinib suppressed expression of Pecam1 in tumors (by 76%, 56% and 21% respectively) and Robo4 (by 56%, 20% and 30% respectively), as well as VEGF regulated genes Ang2 (by 59%, 44% and 41% respectively) and Dll4 (by 78%, 35% and 64% respectively), indicating reduced tumor vessel density and inhibition of VEGF signaling. The three treatments affected a similar number of genes expressed by the tumor cells, including upregulation of hypoxia-induced genes. Conclusions: Our findings indicate that aflibercept treatment of mice induces fewer changes in gene expression in normal tissues than the kinase inhibitors sunitinib or sorafenib, while at the same time produces similar or larger reduction of the tumor vasculature and stroma genes in mouse xenograft models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1023. doi:1538-7445.AM2012-1023