Can anti-vascular endothelial growth factor antibody reverse radiation necrosis? A preclinical investigation

• Published in: Journal of neuro-oncology Vol. 133; no. 1; pp. 9 - 16
• Main Authors: Duan, Chong, Perez-Torres, Carlos J., Yuan, Liya, Engelbach, John A., Beeman, Scott C., Tsien, Christina I., Rich, Keith M., Schmidt, Robert E., Ackerman, Joseph J. H., Garbow, Joel R.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.05.2017; Springer Nature B.V
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - pharmacology; Brain - diagnostic imaging; Brain - drug effects; Brain - pathology; Brain - radiation effects; Brain Injuries - diagnostic imaging; Brain Injuries - drug therapy; Brain Injuries - etiology; Brain Injuries - pathology; Calcification; Calcinosis - diagnostic imaging; Calcinosis - drug therapy; Calcinosis - etiology; Calcinosis - pathology; Diffusion coefficient; Disease Progression; Female; Gangrene; Hypoxia-inducible factor 1; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Hypoxia-inducible factors; Immunohistochemistry; Immunotherapy; Laboratory Investigation; Magnetic Resonance Imaging; Medicine; Medicine & Public Health; Mice, Inbred BALB C; Monoclonal antibodies; Necrosis; Necrosis - diagnostic imaging; Necrosis - drug therapy; Necrosis - etiology; Necrosis - pathology; Neurology; Oncology; Post-irradiation; Radiation Injuries, Experimental - diagnostic imaging; Radiation Injuries, Experimental - drug therapy; Radiation Injuries, Experimental - pathology; Radiation-Protective Agents - pharmacology; Radiosurgery; Random Allocation; Rodents; Targeted cancer therapy; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - immunology; Calcification; HIF-1α; Diffusion; VEGF; Radiation necrosis; Bevacizumab
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-017-2410-3

Anti-vascular endothelial growth factor (anti-VEGF) antibodies are a promising new treatment for late time-to-onset radiation-induced necrosis (RN). We sought to evaluate and validate the response to anti-VEGF antibody in a mouse model of RN. Mice were irradiated with the Leksell Gamma Knife Perfexion™ and then treated with anti-VEGF antibody, beginning at post-irradiation (PIR) week 8. RN progression was monitored via anatomic and diffusion MRI from weeks 4–12 PIR. Standard histology, using haematoxylin and eosin (H&E), and immunohistochemistry staining were used to validate the response to treatment. After treatment, both post-contrast T1-weighted and T2-weighted image-derived lesion volumes decreased ( P  < 0.001), while the lesion volumes for the control group increased. The abnormally high apparent diffusion coefficient (ADC) for RN also returned to the ADC range for normal brain following treatment ( P  < 0.001). However, typical RN pathology was still present histologically. Large areas of focal calcification were observed in ~50% of treated mouse brains. Additionally, VEGF and hypoxia-inducible factor 1-alpha (HIF-1α) were continually upregulated in both the anti-VEGF and control groups. Despite improvements observed radiographically following anti-VEGF treatment, lesions were not completely resolved histologically. The subsequent calcification and the continued upregulation of VEGF and HIF-1α merit further preclinical/clinical investigation.