Acute tumour response to a bispecific Ang-2-VEGF-A antibody: insights from multiparametric MRI and gene expression profiling.
View/ Open
Date
2016-09-06Author
Baker, LCJ
Boult, JKR
Thomas, M
Koehler, A
Nayak, T
Tessier, J
Ooi, C-H
Birzele, F
Belousov, A
Zajac, M
Horn, C
LeFave, C
Robinson, SP
Type
Journal Article
Metadata
Show full item recordAbstract
BACKGROUND: To assess antivascular effects, and evaluate clinically translatable magnetic resonance imaging (MRI) biomarkers of tumour response in vivo, following treatment with vanucizumab, a bispecific human antibody against angiopoietin-2 (Ang-2) and vascular endothelial growth factor-A (VEGF-A). METHODS: Colo205 colon cancer xenografts were imaged before and 5 days after treatment with a single 10 mg kg(-1) dose of either vanucizumab, bevacizumab (anti-human VEGF-A), LC06 (anti-murine/human Ang-2) or omalizumab (anti-human IgE control). Volumetric response was assessed using T2-weighted MRI, and diffusion-weighted, dynamic contrast-enhanced (DCE) and susceptibility contrast MRI used to quantify tumour water diffusivity (apparent diffusion coefficient (ADC), × 10(6) mm(2) s(-1)), vascular perfusion/permeability (K(trans), min(-1)) and fractional blood volume (fBV, %) respectively. Pathological correlates were sought, and preliminary gene expression profiling performed. RESULTS: Treatment with vanucizumab, bevacizumab or LC06 induced a significant (P<0.01) cytolentic response compared with control. There was no significant change in tumour ADC in any treatment group. Uptake of Gd-DTPA was restricted to the tumour periphery in all post-treatment groups. A significant reduction in tumour K(trans) (P<0.05) and fBV (P<0.01) was determined 5 days after treatment with vanucizumab only. This was associated with a significant (P<0.05) reduction in Hoechst 33342 uptake compared with control. Gene expression profiling identified 20 human genes exclusively regulated by vanucizumab, 6 of which are known to be involved in vasculogenesis and angiogenesis. CONCLUSIONS: Vanucizumab is a promising antitumour and antiangiogenic treatment, whose antivascular activity can be monitored using DCE and susceptibility contrast MRI. Differential gene expression in vanucizumab-treated tumours is regulated by the combined effect of Ang-2 and VEGF-A inhibition.
xmlui.dri2xhtml.METS-1.0.item-oa-location
http://www.nature.com/bjc/journal/vaop/ncurrent/pdf/bjc2016236a.pdfCollections
Subject
Cell Line, Tumor
Animals
Humans
Mice
Adenocarcinoma
Colonic Neoplasms
Neovascularization, Pathologic
Angiogenesis Inhibitors
Angiopoietin-2
Vascular Endothelial Growth Factor A
Immunoglobulin E
Antibodies, Bispecific
Antibodies, Monoclonal
Magnetic Resonance Imaging
Tumor Burden
Xenograft Model Antitumor Assays
Gene Expression Profiling
DNA Replication
Gene Expression Regulation, Neoplastic
Molecular Targeted Therapy
Antibodies, Monoclonal, Humanized
Bevacizumab
Omalizumab
Research team
Magnetic Resonance
Pre-Clinical MRI
Language
eng
Date accepted
2016-07-06
License start date
2016-09
Citation
British journal of cancer, 2016, 115 (6), pp. 691 - 702
Publisher
NATURE PUBLISHING GROUP