A new patient-derived orthotopic malignant meningioma model treated with oncolytic herpes simplex virus
A new patient-derived orthotopic malignant meningioma model treated with oncolytic herpes simplex virus
复制标题
DOI：
10.1093/neuonc/now031
复制
发表时间：
2016-09-01
期刊：
影响因子：
15.9
通讯作者：
Wakimoto, Hiroaki
中科院分区：
文献类型：
--
作者：
Nigim, Fares;Esaki, Shin-ichi;Wakimoto, Hiroaki
背景。高级别脑膜瘤（HGMs；世界卫生组织二级和三级）由于复发率高和缺乏有效治疗而构成临床问题。新疗法的临床前开发需要一个疾病模型来概括患者HGM的基因型和表型。溶瘤性单纯疱疹病毒（oHSV）在临床前和临床研究中已显示出对癌症的有效性和安全性，但其在HGM中的应用尚未得到很好的表征。利用免疫缺陷小鼠的肿瘤球培养和连续原位异种移植建立患者源性HGM模型。采用免疫组化、western blot、基因组DNA测序等方法对模型进行病理和分子表征，并与患者肿瘤进行比较。采用细胞活力和体外病毒复制试验以及局部注射G47D后的动物存活分析来评估oHSV G47D的抗hgm作用。我们建立了一个连续移植的原位恶性脑膜瘤模型MN3，肿瘤球植入后3个月内死亡。MN3异种移植物表现出恶性脑膜瘤的病理特征，如高Ki67和高vimentin表达。患者肿瘤和异种移植物的神经纤维蛋白2 （merlin）均为阴性，并且具有相同的NF2突变。溶瘤性HSV G47D在体外有效地扩散和杀死MN3细胞，以及其他患者来源的HGM细胞系。G47D治疗可显著延长MN3硬膜下肿瘤小鼠的存活时间。我们建立了一个新的患者源性脑膜瘤模型，这将使HGM的靶向治疗方法的研究成为可能。基于这些研究，考虑G47D治疗HGM的临床试验是合理的。
Background. Higher-grade meningiomas (HGMs; World Health Organization grades II and III) pose a clinical problem due to high recurrence rates and the absence of effective therapy. Preclinical development of novel therapeutics requires a disease model that recapitulates the genotype and phenotype of patient HGM. Oncolytic herpes simplex virus (oHSV) has shown efficacy and safety in cancers in preclinical and clinical studies, but its utility for HGM has not been well characterized.Methods. Tumorsphere cultures and serial orthotopic xenografting in immunodeficient mice were used to establish a patientderived HGM model. The model was pathologically and molecularly characterized by immunohistochemistry, western blot, and genomic DNA sequencing and compared with the patient tumor. Anti-HGM effects of oHSV G47D were assessed using cell viability and virus replication assays in vitro and animal survival analysis following intralesional injections of G47D.Results. We established a serially transplantable orthotopic malignant meningioma model, MN3, which was lethal within 3 months after tumorsphere implantation. MN3 xenografts exhibited the pathological hallmarks of malignant meningioma such as high Ki67 and vimentin expression. Both the patient tumor and xenografts were negative for neurofibromin 2 (merlin) and had the identical NF2 mutation. Oncolytic HSV G47D efficiently spread and killed MN3 cells, as well as other patient-derived HGM lines in vitro. Treatment with G47D significantly extended the survival of mice bearing subdural MN3 tumors.Conclusions. We established a new patient-derived meningioma model that will enable the study of targeted therapeutic approaches for HGM. Based on these studies, it is reasonable to consider a clinical trial of G47D for HGM.