NF2相关神经鞘瘤病(NF2-SWN)是一种需要新解决方案的疾病。NF2-SWN的标志,显性遗传性肿瘤形成综合征,是双侧前庭神经鞘瘤(VSs),逐渐扩大,导致感觉神经性听力损失,耳鸣,面部无力,和疼痛转化为社会障碍和临床抑郁症。生长的VSs的标准治疗包括手术和放射治疗(RT);然而,两者都有进一步神经损伤的风险,可能导致耳聋和面神经麻痹。由此产生的痛苦和堕落,结合治疗选择的匮乏,使NF2-SWN的有效治疗成为尚未满足的主要医疗需求。更好地理解这些机制对于开发新的治疗靶点以控制肿瘤生长和改善患者的生活质量至关重要。以前,我们建立了第一个原位桥小脑角小鼠模型,忠实地模仿肿瘤引起的听力损失。在这个模型中,我们观察到小鼠表现出共济失调和前庭功能障碍的症状。因此,我们进一步开发了一组适用于小鼠VS模型的五个测试,并研究了肿瘤生长和治疗如何影响步态,协调,和运动功能。使用这个共济失调测试小组,我们证明共济失调和运动功能随着肿瘤进展而恶化。我们进一步证明(i)用抗VEGF治疗导致肿瘤大小减小,减轻共济失调,(ii)克唑替尼治疗稳定了肿瘤生长,并改善了共济失调和圆棒表现;(iii)氯沙坦治疗不影响肿瘤生长,也不改善共济失调或运动功能。我们的研究表明,这些方法,与听力测试配对,能够全面评估肿瘤诱导的神经功能缺损,并有助于评估新疗法的有效性,以改善NF2治疗。
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.