NF2-related Schwannomatosis (NF2-SWN) is a disease that needs new solutions. The hallmark of NF2-SWN, a dominantly inherited neoplasia syndrome, is bilateral vestibular schwannomas (VSs), which progressively enlarge, leading to sensorineural hearing loss, tinnitus, facial weakness, and pain that translates to social impairment and clinical depression. Standard treatments for growing VSs include surgery and radiation therapy (RT); however, both carry the risk of further nerve damage that can result in deafness and facial palsy. The resultant suffering and debility, in combination with the paucity of therapeutic options, make the effective treatment of NF2-SWN a major unmet medical need. A better understanding of these mechanisms is essential to developing novel therapeutic targets to control tumor growth and improve patients’ quality of life. Previously, we developed the first orthotopic cerebellopontine angle mouse model of VSs, which faithfully mimics tumor-induced hearing loss. In this model, we observed that mice exhibit symptoms of ataxia and vestibular dysfunction. Therefore, we further developed a panel of five tests suitable for the mouse VS model and investigated how tumor growth and treatment affect gait, coordination, and motor function. Using this panel of ataxia tests, we demonstrated that both ataxia and motor function deteriorated concomitantly with tumor progression. We further demonstrated that (i) treatment with anti-VEGF resulted in tumor size reduction, mitigated ataxia, and improved rotarod performance; (ii) treatment with crizotinib stabilized tumor growth and led to improvements in both ataxia and rotarod performance; and (iii) treatment with losartan did not impact tumor growth nor ameliorate ataxia or motor function. Our studies demonstrated that these methods, paired with hearing tests, enable a comprehensive evaluation of tumor-induced neurological deficits and facilitate the assessment of the effectiveness of novel therapeutics to improve NF2 treatments.
NF2相关神经鞘瘤病（NF2-SWN）是一种亟需新解决方案的疾病。作为常染色体显性遗传的肿瘤综合征，NF2-SWN的标志性特征是双侧前庭神经鞘瘤（VSs），这些肿瘤会进行性增大，导致感音神经性听力损失、耳鸣、面部肌力减弱及疼痛，进而引发社交障碍和临床抑郁。针对进展性VSs的标准治疗包括手术和放射治疗（RT），但两者均存在进一步神经损伤的风险，可能导致耳聋和面瘫。由此带来的痛苦与功能障碍，加之治疗选择有限，使得NF2-SWN的有效治疗成为尚未满足的重大医疗需求。深入理解其发病机制对于开发控制肿瘤生长、改善患者生活质量的新型治疗靶点至关重要。此前，我们成功构建了首个忠实模拟肿瘤性听力损失的小鼠前庭神经鞘瘤桥小脑角原位模型。在该模型中，我们观察到小鼠表现出共济失调和前庭功能障碍症状。为此，我们进一步开发了一套适用于小鼠VS模型的五项测试方法，系统研究肿瘤生长及治疗对步态、协调性和运动功能的影响。通过这套共济失调测试组合，我们证实共济失调与运动功能会随肿瘤进展同步恶化。进一步研究发现：（1）抗VEGF治疗可缩小肿瘤体积、减轻共济失调症状并改善转棒测试表现；（2）克唑替尼治疗能稳定肿瘤生长，同时改善共济失调和转棒测试表现；（3）氯沙坦治疗对肿瘤生长、共济失调及运动功能均无改善作用。本研究表明，这些方法结合听力测试，能够全面评估肿瘤引起的神经功能缺损，并为评估改善NF2治疗的新型疗法效果提供有效工具。
肿瘤(癌症)患者之家