Anti-VEGF agents in metastatic colorectal cancer (mCRC): are they all alike? - PubMed (original) (raw)

Anti-VEGF agents in metastatic colorectal cancer (mCRC): are they all alike?

Muhammad Wasif Saif. Cancer Manag Res. 2013.

Abstract

Bevacizumab is a monoclonal antibody that binds and neutralizes vascular endothelial growth factor (VEGF)-A, a key player in the angiogenesis pathway. Despite benefits of bevacizumab in cancer therapy, it is clear that the VEGF pathway is complex, involving multiple isoforms, receptors, and alternative ligands such as VEGF-B, and placental growth factor, which could enable escape from VEGF-A-targeted angiogenesis inhibition. Recently developed therapies have targeted other ligands in the VEGF pathway (eg, aflibercept, known as ziv-aflibercept in the United States), VEGF receptors (eg, ramucirumab), and their tyrosine kinase signaling (ie, tyrosine kinase inhibitors). The goal of the current review was to identify comparative preclinical data for the currently available VEGF-targeted therapies. Sources were compiled using PubMed searches (2007 to 2012), using search terms including, but not limited to: "bevacizumab," "aflibercept," "ramucirumab," and "IMC-18F1." Two preclinical studies were identified that compared bevacizumab and the newer agent, aflibercept. These studies identified some important differences in binding and pharmacodynamic activity, although the potential clinical relevance of these findings is not known. Newer antiangiogenesis therapies should help further expand treatment options for colorectal and other cancers. Comparative preclinical data on these agents is currently lacking.

Keywords: aflibercept; antiangiogenesis; metastatic colorectal cancer (mCRC); tyrosine kinase inhibitor (TKI); vascular endothelial growth factor (VEGF).

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Figures

Figure 1

Figure 1

Diversity of VEGF and PlGF isoforms: homo- and heterodimers. Notes: The VEGF ligands, VEGF-A, VEGF-B, and PlGF can all interact with VEGFR-1, and the illustration provides an example of how diversity in isoforms can result in a wide array of signaling molecules that can interact with the receptor. The four PlGF isoforms can homo- and heterodimerize with any of six distinct isoforms of VEGF-A, as can the two isoforms of VEGF-B, resulting in many combinations that can potentially exhibit different biological activity.,, Abbreviations: PlGF, placental growth factor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Figure 2

Figure 2

VEGF ligands, receptors, and inhibitors.,,, Adapted with permission from Takahashi S. Vascular endothelial growth factor (VEGF), VEGF receptors and their inhibitors for antiangiogenic tumor therapy. Biol Pharm Bull. 2011;34(12):1785–1788. Abbreviations: PlGF, placental growth factor; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Figure 3

Figure 3

Molecular masses of aflibercept-VEGF-A and bevacizumab-VEGF-A complexes. (A) Using a 1:2 molar ratio of aflibercept to VEGF 165, discrete peaks were observed at 17 mL and 14.5 mL. In contrast, a 1:2 molar ratio of bevacizumab to VEGF 165 revealed a heterogeneous multimeric complex that ranged in molar mass from 370 kDa to 2000 kDa. (B) One milligram of a preformed complex of aflibercept (VEGF Trap) and VEGF 165 or bevacizumab and VEGF 165 were injected into the left ventricle of 2- to 3-month-old C57bl6 mice. After 10 minutes, the mice were killed, and their kidneys were processed for immunocytochemistry, using an antihuman Fc reporter antibody to the human Fc moiety present on both aflibercept and bevacizumab. Significant staining was observed in the glomeruli of bevacizumab/VEGF-treated mice but not in the glomeruli of aflibercept/VEGF-treated mice (white arrows). Reprinted with permission from Rudge JS, Holash J, Hylton D, et al. VEGF Trap complex formation measures production rates of VEGF, providing a biomarker for predicting efficacious angiogenic blockade. Proc Natl Acad Sci U S A. 2007;104(47):18363–18370. Copyright 2007 National Academy of Sciences, USA. Abbreviations: RIU, refractive index units; VEGF, vascular endothelial growth factor.

Figure 4

Figure 4

(A) Effect of aflibercept and bevacizumab on luciferase activity in cells expressing VEGFR-1 stimulated by VEGF-A 121. (B) Effect of aflibercept and bevacizumab on luciferase activity in cells expressing VEGFR-1 stimulated by VEGF-A 165. (C) Effect of aflibercept and bevacizumab on luciferase activity in cells expressing VEGFR-1 stimulated by PlGF. Adapted from Papadopoulos N. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171–185. The article/figure is published under Creative Commons License 2.0 CC-BY. Abbreviations: RLU, relative luciferase units; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

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