Anti-VEGF treatment improves neurological function and augments radiation response in NF2 schwannoma model

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 112; no. 47; pp. 14676 - 14681
• Main Authors: Gao, Xing, Zhao, Yingchao, Stemmer-Rachamimov, Anat O., Liu, Hao, Huang, Peigen, Chin, ShanMin, Selig, Martin K., Plotkin, Scott R., Jain, Rakesh K., Xu, Lei
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 24.11.2015; National Acad Sciences
• Subjects: Animals; Antibodies - pharmacology; Antibodies - therapeutic use; Biological Sciences; Cell Line, Tumor; Disease Models, Animal; Dose-Response Relationship, Radiation; Edema; Edema - complications; Edema - pathology; Hearing loss; Humans; Mice; Muscular Atrophy - complications; Muscular Atrophy - pathology; Nerve Regeneration - drug effects; Neurofibromatosis 2 - complications; Neurofibromatosis 2 - physiopathology; Neurofibromin 2 - deficiency; Neurofibromin 2 - metabolism; Neuroma, Acoustic - blood supply; Neuroma, Acoustic - drug therapy; Neuroma, Acoustic - physiopathology; Neuroma, Acoustic - radiotherapy; Oxygen; Oxygenation; Radiation therapy; Radiation Tolerance - drug effects; Rotarod Performance Test; Sciatic Nerve - drug effects; Sciatic Nerve - pathology; Sciatic Nerve - ultrastructure; Signal Transduction - drug effects; Toxicity; Treatment Outcome; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - metabolism; anti-VEGF; neurological function; radiation; NF2 schwannoma model
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1512570112

Hearing loss is the main limitation of radiation therapy for vestibular schwannoma (VS), and identifying treatment options that minimize hearing loss are urgently needed. Treatment with bevacizumab is associated with tumor control and hearing improvement in neurofibromatosis type 2 (NF2) patients; however, its effect is not durable and its mechanism of action on nerve function is unknown. We modeled the effect anti-VEGF therapy on neurological function in the sciatic nerve model and found that it improves neurological function by alleviating tumor edema, which may further improve results by decreasing muscle atrophy and increasing nerve regeneration. Using a cranial window model, we showed that anti-VEGF treatment may achieve these effects via normalizing the tumor vasculature, improving vessel perfusion, and delivery of oxygenation. It is known that oxygen is a potent radiosensitizer; therefore, we further demonstrated that combining anti-VEGF with radiation therapy can achieve a better tumor control and help lower the radiation dose and, thus, minimize radiation-related neurological toxicity. Our results provide compelling rationale for testing combined therapy in human VS.