| Abstract: | ![]()
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.Neurofibromatosis type 2 (NF2) is a dominantly inherited genetic condition with a birth prevalence of 1 in 25,000 (1). Bilateral vestibular schwannomas (VS), which are benign tumors composed of neoplastic Schwann cells that arise from the eighth cranial nerve, are the hallmark of NF2 (2). Standard approaches for treatment of growing VS include surgical removal and radiation therapy (RT). Hearing loss is the main limitation of radiation therapy for VS. For patients with sporadic VS who do not have NF2, RT is associated with long-term tumor control rates exceeding 95%. However, hearing preservation rates after radiation range from 50% to 80% (3, 4). Outcomes after radiation for patients with NF2 are inferior to those for sporadic patients, with short-term local tumor control rates approximately 80–85% and hearing preservation rates <50% (3). Thus, the identification of a novel adjunct therapy to enhance radiosensitivity while minimizing toxicity-related hearing loss in VS is urgently needed.Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) are expressed in VS, and its expression level positively correlates with schwannoma growth rate (5–7). In a retrospective review of 31 NF2 patients, treatment with bevacizumab, a humanized monoclonal antibody that specifically neutralizes VEGF-A, was associated with a reduction in the volume of most growing VS. More importantly, bevacizumab treatment improved hearing in 57% patients (7). Despite this progress, a number of challenges remain (8). First, not all NF2 patients respond to bevacizumab; second, the hearing response is not durable in all patients; and third, some patients are unable to tolerate long-term bevacizumab treatment. Studies to understand the mechanisms of anti-VEGF therapy-induced tumor growth inhibition and hearing improvement in schwannomas are urgently needed to optimize this therapy.In our study, first, we used the sciatic nerve model to characterize the effect and mechanisms of anti-VEGF treatment on neurological function. We revealed that anti-VEGF treatment alleviates tumor edema, which may further result in decreasing muscle atrophy and increasing nerve regeneration and, thus, improves neurological function. Second, we used the intracranial window model to monitor in real time the effect of anti-VEGF treatment on tumor vasculature. We showed that anti-VEGF treatment transiently normalizes the tumor vasculature, leading to improved perfusion and oxygen delivery. Using intravital microscopy imaging technique, we further defined the timing of this transient effect, termed the “normalization window,” in schwannoma models. Because oxygen is a potent radiosensitizer, finally, we showed that radiation therapy applied during the normalization window is most effective, and combined anti-VEGF and radiation therapy is superior to each monotherapy. Anti-VEGF and radiation combination therapy may thus help reduce the dose of each therapy and minimize treatment-associated adverse effect in NF2 patients. |
