Departments of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Otology and Neurotology, University Hospital of Lille, and INSERM U1008, University of Lille, Lille, France.
J Neurooncol. 2017 Oct;135(1):47-56. doi: 10.1007/s11060-017-2567-9. Epub 2017 Jul 22.
Neurofibromatosis type 2 (NF2), a neurogenetic condition manifest by peripheral nerve sheath tumors (PNST) throughout the neuroaxis for which there are no approved therapies. In vitro and in vivo studies presented here examine agents targeting signaling pathways, angiogenesis, and DNA repair mechanisms. In vitro dose response assays demonstrated potent activity of lapatinib and nilotinib against the mouse schwannoma SC4 (Nf2 ) cell line. We then examined the efficacy of everolimus, nilotinib, lapatinib, bevacizumab and radiation (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 ) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748). Lapatinib, nilotinib and RT significantly reduced tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas bevacizumab and everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed nilotinib or lapatinib as single agents (nilotinib vs. nilotinib + RT, p = 0.0001; lapatinib versus lapatinib + RT, p < 0.0001) with no observed toxicity. There was no re-growth of tumors even 14 days after treatment was stopped. The combination of either lapatinib or nilotinib with RT resulted in greater delays in tumor growth rate than any modality alone. This data suggest that concurrent low dose RT and targeted therapy may have a role in addressing progressive PNST in patients with NF2.
神经纤维瘤病 2 型（NF2）是一种神经遗传性疾病，表现为沿整个神经系统分布的外周神经鞘肿瘤（PNST），目前尚无批准的治疗方法。本文介绍了一些针对信号通路、血管生成和 DNA 修复机制的靶向药物的体外和体内研究。体外剂量反应试验表明，拉帕替尼和尼罗替尼对小鼠雪旺细胞瘤 SC4（Nf2）细胞系具有很强的活性。然后，我们研究了依维莫司、尼罗替尼、拉帕替尼、贝伐珠单抗和放射治疗（RT）作为单一和联合疗法在 NF2-PNST 模型的侧腹和坐骨神经中的疗效。数据使用广义线性模型、两样本 t 检验和配对 t 检验以及线性回归模型进行分析。植入侧腹或坐骨神经的 SC4（Nf2）细胞的生长速度相似（p=0.9748）。与对照组相比，拉帕替尼、尼罗替尼和 RT 在体内侧腹模型中显著降低了肿瘤生长速度（p=0.0025、0.0062 和 0.009，分别），而贝伐珠单抗和依维莫司则没有。在 NF2 相关 PNST 的体内坐骨神经模型中，对表现最好的药物进行了测试，其中化疗联合放疗优于尼罗替尼或拉帕替尼作为单一药物（尼罗替尼与尼罗替尼联合放疗相比，p=0.0001；拉帕替尼与拉帕替尼联合放疗相比，p<0.0001），且未观察到毒性。即使在治疗停止 14 天后，也没有肿瘤再生长。与任何单一治疗方式相比，拉帕替尼或尼罗替尼与 RT 联合使用导致肿瘤生长速度的延迟更大。这些数据表明，在 NF2 患者中，低剂量 RT 与靶向治疗同时进行可能在治疗进行性 PNST 方面发挥作用。
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