Abstract 4809: Enhanced activity of aflibercept compared to bevacizumab in a patient-derived xenograft colorectal cancer model is associated with reduced tumor vascularity in humanized VEGF mice
Authors: Abrahams Cristina L. , Winters Laura D. , Li Baosheng , Parveen Asma A. , Kloss Tatjana , Bagley Rebecca G. , Bergstrom Donald A. , Thurston Gavin , Chiron Marielle 
Published: May 2015

Abstract
VEGF inhibitors aflibercept (ziv-aflibercept in USA) and bevacizumab target vascular endothelial growth factor A (VEGF-A), and are approved for the 2nd line treatment of metastatic colorectal cancer (CRC) in combination with distinct chemotherapy regimens and after different 1st line therapies. Although both aflibercept and bevacizumab bind to VEGF-A (herein referred to as VEGF), aflibercept blocks additional VEGF family ligands PlGF and VEGF-B, which bind VEGF receptor 1 (VEGFR1), whereas bevacizumab does not. We recently utilized patient-derived xenograft (PDX) models of CRC to compare the pharmacological activity of aflibercept and bevacizumab. In a screening study in nude mice, aflibercept showed more potent anti-tumor activity in 39/48 CRC PDX compared to bevacizumab (Chiron M. et al, AACR-NCI-EORTC 2013). In these PDX, tumor levels of tumor-derived human VEGF (hVEGF) were much higher than host murine VEGF (mVEGF), however, a potential limitation was that bevacizumab does not bind mVEGF. To further rule out any contribution from mVEGF and to determine whether tumor cell expression of VEGFR1 played a role in the differential responses, we compared the effects of aflibercept and bevacizumab on selected PDX CRC tumors in SCID mice genetically engineered to express hVEGF from the mVEGF locus. In humanized VEGF mice, aflibercept was more potent in 3/7 PDX compared with bevacizumab but equivalent in 4/7 PDX. Tumors in PDX IMM-Colo-0018 and IMM-Colo-0010, with high and low VEGFR1 expression, respectively, regressed in response to aflibercept while bevacizumab resulted in growth stasis. PDX model CXF280 with high VEGFR1 expression, consistently showed significantly greater response to aflibercept in comparison to bevacizumab. In contrast, PDX model CFX260, also with high VEGFR1 expression, responded equally well to both drugs. There was no CRC PDX in humanized VEGF mice in which the activity of bevacizumab was greater than aflibercept. Immunohistochemistry analysis revealed that improved efficacy of aflibercept treatment over bevacizumab was associated with a greater reduction of tumor vessel density and sprouting in CFX280 tumors. Cumulatively, these results suggest that aflibercept is more potent than bevacizumab in certain PDX CRC tumor models. In this limited subset of PDX CRC models, differences in pharmacological activity observed between aflibercept and bevacizumab in humanized VEGF mice do not appear to correlate with tumor cell expression of VEGFR1, but instead are associated with a greater reduction of tumor blood vessels. We are further investigating the role of VEGFR1 and other factors that may explain enhanced anti-tumor efficacy of aflibercept in PDX CRC models in humanized mice. The results suggest that CRC patient subsets may exist where aflibercept is more active than therapies targeting only VEGF-A.
Citation Format: Cristina L. Abrahams, Laura D. Winters, Baosheng Li, Asma A. Parveen, Tatjana Kloss, Rebecca G. Bagley, Donald A. Bergstrom, Gavin Thurston, Marielle Chiron. Enhanced activity of aflibercept compared to bevacizumab in a patient-derived xenograft colorectal cancer model is associated with reduced tumor vascularity in humanized VEGF mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4809. doi:10.1158/1538-7445.AM2014-4809