Lu Simeng, Yin Zhenzhen, Chen Jie, Wu Limeng, Sun Yao, Gao Xing, Huang Peigen, Jordan Justin T, Plotkin Scott R, Xu Lei
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha 410008, China.
Cancers (Basel). 2024 May 22;16(11):1961. doi: 10.3390/cancers16111961.
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.
与神经纤维瘤病2型相关的神经鞘瘤病（NF2-SWN）是一种需要新解决方案的疾病。NF2-SWN是一种常染色体显性遗传的肿瘤综合征，其特征是双侧前庭神经鞘瘤（VSs），这些肿瘤会逐渐增大，导致感音神经性听力丧失、耳鸣、面部无力和疼痛，进而导致社会功能障碍和临床抑郁。对于不断生长的VSs，标准治疗方法包括手术和放射治疗（RT）；然而，这两种治疗方法都有进一步损伤神经的风险，可能导致耳聋和面神经麻痹。由此产生的痛苦和虚弱，再加上治疗选择的匮乏，使得NF2-SWN的有效治疗成为一项重大的未满足医疗需求。更好地理解这些机制对于开发控制肿瘤生长和改善患者生活质量的新治疗靶点至关重要。此前，我们开发了首个VSs的原位小脑脑桥角小鼠模型，该模型能如实地模拟肿瘤引起的听力丧失。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模型的五项测试，并研究了肿瘤生长和治疗如何影响步态、协调性和运动功能。使用这组共济失调测试，我们证明共济失调和运动功能会随着肿瘤进展而同时恶化。我们进一步证明：（i）抗血管内皮生长因子（VEGF）治疗可使肿瘤缩小，减轻共济失调，并改善转棒试验表现；（ii）克唑替尼治疗可稳定肿瘤生长，并使共济失调和转棒试验表现均得到改善；（iii）氯沙坦治疗对肿瘤生长没有影响，也不能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相结合，能够全面评估肿瘤引起的神经功能缺损，并有助于评估新型疗法改善NF2治疗效果的有效性。
