Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 112, Issue 47, Pages 14676-14681Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1512570112
Keywords
NF2 schwannoma model; anti-VEGF; neurological function; radiation
Categories
Funding
- Children's Tumor Foundation Clinical Research Award
- American Cancer Society Research Scholar Award
- CTF Drug Discovery Initiative
- Ira Spiro Award
- NIH/National Cancer Institute [P01CA080214, P50CA165962]
- Outstanding Investigator Grant [R35CA197743]
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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.
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