The efficacy of lapatinib and nilotinib in combination with radiation therapy in a model of NF2 associated peripheral schwannoma
The efficacy of lapatinib and nilotinib in combination with radiation therapy in a model of NF2 associated peripheral schwannoma
复制标题
拉帕替尼和尼罗替尼联合放射治疗在 NF2 相关外周神经鞘瘤模型中的疗效
作者：
Iddo Paldor;S. Abbadi;N. Bonne;X. Ye;F. Rodriguez;David Rowshanshad;MariaLisa S. M. Itzoe;Veronica Vigilar;M. Giovannini;H. Brem;J. Blakeley;B. Tyler
2型神经纤维瘤病（NF2）是一种神经遗传疾病，表现为周围神经鞘肿瘤（PNST），贯穿整个神经轴，目前尚无批准的治疗方法。本文提出的体外和体内研究考察了靶向信号通路、血管生成和DNA修复机制的药物。体外剂量反应试验表明，拉帕替尼和尼洛替尼对小鼠神经鞘瘤SC4 （Nf2−/−）细胞系具有有效的活性。然后，我们检查了依维莫司、尼罗替尼、拉帕替尼、贝伐单抗和放疗（RT）作为单独和联合治疗在体内NF2-PNST模型的侧腹和坐骨神经的疗效。数据分析采用广义线性模型、双样本t检验和配对t检验以及线性回归模型。SC4（Nf2−/−）细胞移植于侧腹神经或坐骨神经的生长速率相似（p = 0.9748）。在体内侧腹模型中，拉帕替尼、尼罗替尼和RT显著降低肿瘤生长速度（p分别= 0.0025、0.0062和0.009），而贝伐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测试了表现最好的药物，其中放化疗优于尼洛替尼或拉帕替尼作为单一药物（尼洛替尼vs尼洛替尼+ RT， p = 0.0001；拉帕替尼vs拉帕替尼+ RT， p < 0.0001），未观察到毒性。停止治疗14天后，肿瘤仍未再生长。拉帕替尼或尼洛替尼联合放疗比单独使用任何一种治疗方式都更能延缓肿瘤的生长速度。这些数据表明，同时进行低剂量放疗和靶向治疗可能在NF2患者的进行性PNST中发挥作用。
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.
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DOI：
10.1016/j.hoc.2011.04.008
发表时间：
2011-08
期刊：
Hematology/oncology clinics of North America
影响因子：
--
作者：
Voss MH;Molina AM;Motzer RJ
通讯作者：
Motzer RJ
影响因子：
4.8
作者：
Wong, Hon-Kit;Shimizu, Akio;Jain, Rakesh K.
通讯作者：
Jain, Rakesh K.
影响因子：
2.8
作者：
Stamenkovic I;Yu Q
通讯作者：
Yu Q
影响因子：
15.9
作者：
Jessen, Walter J.;Miller, Shyra J.;Ratner, Nancy
通讯作者：
Ratner, Nancy