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首页 » BIOON报道 » Neuro-Oncol:粘液瘤病毒和雷帕霉素的结合性疗法或可有效抵御致死性脑瘤

Neuro-Oncol:粘液瘤病毒和雷帕霉素的结合性疗法或可有效抵御致死性脑瘤

来源:生物谷 2013-06-23 23:03

2013年6月24日 讯 /生物谷BIOON/ --近日,刊登在国际杂志Neuro-Oncology上的一篇研究报告中,来自莫菲特癌症研究中心的研究者通过研究表示,粘液瘤病毒和免疫抑制剂雷帕霉素的结合性疗法可有效感染及杀灭多形性胶质母细胞瘤,其实一种常见的致死性脑瘤。

研究者Peter A. Forsyth表示,这种疗法的结合可有效杀灭所有的脑瘤干细胞以及差异化的多形性胶质母细胞瘤;尽管药物替莫唑胺可以改善多形性胶质母细胞瘤患者的生存期,但是耐药性也是一大障碍,溶瘤病毒可以有效感染病破坏癌细胞,这就为克服疗法耐受性提供了希望。

溶瘤病毒可以对肿瘤进行多面攻击,而且可以通过病毒感染以及刺激机体免疫系统来杀灭肿瘤。这些多重途径就可以绕过经典的耐药机制从而发挥更大的效用。许多溶瘤病毒,其可以单独作用也可以通过结合小分子抑制剂来发挥作用,在治疗恶性神经胶质瘤表现出极大潜力,然而其在杀灭癌细胞上并没有表现出多大作用,或许存在两大障碍,一种是病人机体的抗病毒免疫应答,另一种是病毒的分散非常有限所以作用较为有限。

研究者Forsyth说,基于此前粘液瘤病毒的研究,我们考虑其或许是一种更为有效的溶瘤病毒来抵御脑瘤干细胞。

研究者发现脑瘤干细胞对于实验室培养条件下(体外研究)以及动物模型(体内研究)的粘液瘤病毒较为敏感,包括对替莫唑胺耐药的细胞系。同时研究者表示,携带有雷帕霉素的粘液瘤病毒或许是一种更为有效的结合性疗法。

雷帕霉素可增强脑瘤干细胞感染的机制并不清楚,而且疗法的结合并不能彻底治愈疾病,与此同时研究者正在调查别的可以改善粘液瘤病毒作用效果的药物,而且研究者也对粘液瘤病毒的其它菌株类型进行了有效性的评估。

最后研究者表示,尽管我们的研究使用粘液瘤病毒来感染和杀灭脑瘤细胞,其可以在一定程度增强临床应用,我们的模型将需要进行临床试验来确定其对病人是否安全,基于前期的实验结果,我们期待颅内注射粘液瘤病毒的疗法的安全性和疗法有效性,相关研究由NIH提供资助。(生物谷Bioon.com)

Treating brain tumor–initiating cells using a combination of myxoma virus and rapamycin

Franz J. Zemp†, Xueqing Lun†, Brienne A. McKenzie, Hongyuan Zhou, Lori Maxwell, Beichen Sun, John J.P. Kelly, Owen Stechishin, Artee Luchman, Samuel Weiss, J. Gregory Cairncross, Mark G. Hamilton, Brian A. Rabinovich, Masmudur M. Rahman, Mohamed R. Mohamed, Sherin Smallwood, Donna L. Senger, John Bell, Grant McFadden and Peter A. Forsyth

Background Intratumoral heterogeneity in glioblastoma multiforme (GBM) poses a significant barrier to therapy in certain subpopulation such as the tumor-initiating cell population, being shown to be refractory to conventional therapies. Oncolytic virotherapy has the potential to target multiple compartments within the tumor and thus circumvent some of the barriers facing conventional therapies. In this study, we investigate the oncolytic potential of myxoma virus (MYXV) alone and in combination with rapamycin in vitro and in vivo using human brain tumor–initiating cells (BTICs). Methods We cultured fresh GBM specimens as neurospheres and assayed their growth characteristics in vivo. We then tested the susceptibility of BTICs to MYXV infection with or without rapamycin in vitro and assessed viral biodistribution/survival in vivo in orthotopic xenografts. Results The cultured neurospheres were found to retain stem cell markers in vivo, and they closely resembled human infiltrative GBM. In this study we determined that (i) all patient-derived BTICs tested, including those resistant to temozolomide, were susceptible to MYXV replication and killing in vitro; (ii) MYXV replicated within BTICs in vivo, and intratumoral administration of MYXV significantly prolonged survival of BTIC-bearing mice; (iii) combination therapy with MYXV and rapamycin improved antitumor activity, even in mice bearing “advanced” BTIC tumors; (iv) MYXV treatment decreased expression of stem cell markers in vitro and in vivo. Conclusions Our study suggests that MYXV in combination with rapamycin infects and kills both the BTICs and the differentiated compartments of GBM and may be an effective treatment even in TMZ-resistant patients.

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