Vascular endothelial growth factor as an anti-angiogenic target for cancer therapy

Abstract

New blood vessel formation (angiogenesis) is fundamental to tumor growth, invasion, and metastatic dissemination. The vascular endothelial growth factor (VEGF) signaling pathway plays pivotal roles in regulating tumor angiogenesis. VEGF as a therapeutic target has been validated in various types of human cancers. Different agents including antibodies, aptamers, peptides, and small molecules have been extensively investigated to block VEGF and its pro-angiogenic functions. Some of these agents have been approved by FDA and some are currently in clinical trials. Combination therapies are also being pursued for better tumor control. By providing comprehensive real-time information, molecular imaging of VEGF pathway may accelerate the drug development process. Moreover, the imaging will be of great help for patient stratification and therapeutic effect monitoring, which will promote effective personalized molecular cancer therapy. This review summarizes the current status of tumor therapeutic agents targeting to VEGF and the applications of VEGF related molecular imaging.

Figures

Figure 1. Protein and mRNA products of human vascular endothelial growth factor A (VEGF-A)

A The pro-angiogenic isoforms (VEGF-Axxx, left) are generated by proximal splice site (PSS) selection in exon 8. B Protein structure of VEGF-A containing the dimerization sites and binding sites for heparin, VEGF-A receptor 1 (VEGFR1; encoded by exon 3) and VEGFR2 (encoded by exon 4), which are present in all isoforms. C The anti-angiogenic family (VEGF-Axxxb, right) from exon 8 distal splice site (DSS) choice. UTR, untranslated region. Reprinted with the permission of reference (64).

Figure 2

Binding specificity of various vascular endothelial growth factor (VEGF) family members and their receptors. VEGF-E and VEGF-F are exogenous subtypes.

Figure 3

VEGF targeted and anti-VEGF drugs.

Figure 4

Vessel regression and tumor necrosis following shut off of VEGF expression. Hematoxylin and eosin staining of sections from C6 tumors grown in Nude mice for 2 weeks in the absence of tetracycline and resected 0 h (A), 24 h (B), 48 h (C), 72 h (D), 4 days (E), and 5 days (F) after administration of tetracycline to shut off expression of VEGF from the transfected VEGF165. n, Necrosis. Reprinted with permission of reference (84)

Figure 5

Molecular imaging of tumor angiogenesis. A MicroPET of 64Cu-DOTA-VEGF121 in U87MG tumor-bearing mice. Serial small animal PET scans of large and small U87MG tumor-bearing mice injected intravenously with 5–10 MBq of 64Cu-DOTA-VEGF121 ( 2–4 μg of VEGF121). Mice injected with 64Cu-DOTA-VEGF121 30 min after injection of 100 μg VEGF121 are also shown (denoted as “Small tumor + block”). Tumors are indicated by arrows. Reprinted with the permission of reference (200). B Transverse color-coded US images of subcutaneous 9-mm malignant glioma tumor (arrows) in same nude mouse. Images obtained 4 minutes after intravenous administration of anti-VEGFR2 monoclonalantibody conjugated microbubbles (MBV, left), IgG conjugated microbubbles (MBC, middle) or non-targeted microbubbles (MBN, right). Differences in video intensity from subtraction of pre- and postdestruction images (green) on gray scale images were higher with MBV than with MBC. No signal was detected after MBN application. Reprinted with the permission of reference (208).