Differential Susceptibility of Ex Vivo Primary Glioblastoma Tumors to Oncolytic Effect of Modified Zika Virus.
Differential Susceptibility of Ex Vivo Primary Glioblastoma Tumors to Oncolytic Effect of Modified Zika Virus.
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作者：
胶质母细胞瘤（GBM）是最常见的原发性恶性脑肿瘤，是一种高度致命的癌症，治疗方案非常有限。肿瘤细胞群体的高度异质性和这些细胞的侵袭性降低了传统癌症治疗的可能疗效，因此需要研究新的治疗方案。使用溶瘤病毒作为潜在治疗方法已经研究了一段时间。寨卡病毒（ZIKV）已证明对GBM干细胞（GSC）具有亲瘤性和溶瘤作用。为了解决对安全有效的GBM治疗的需求，我们设计了减毒的ZIKV毒株（ZOL-1），与未修饰的ZIKV相比，其在小鼠模型中不引起麻痹或神经系统疾病。重要的是，我们发现患者来源的GBM肿瘤对ZOL-1介导的肿瘤细胞杀伤表现出易感性（应答者）和非易感性（非应答者），如ZOL-1治疗后的差异性凋亡细胞死亡和细胞活力所证明的。在反应细胞中观察到的溶瘤作用在体外神经球模型和体内异种移植后均观察到。最后，我们观察到在无应答GBM中使用ZOL-1作为与多种PI 3 K-AKT抑制剂的组合疗法导致增强的化疗功效。总之，本研究确立了ZOL-1作为一种安全有效的治疗GBM的方法，并为进一步研究提供了基础，以评估其作为其他化疗和激酶抑制剂的有效佐剂的潜力。
Glioblastoma (GBM), the most common primary malignant brain tumor, is a highly lethal form of cancer with a very limited set of treatment options. High heterogeneity in the tumor cell population and the invasive nature of these cells decrease the likely efficacy of traditional cancer treatments, thus requiring research into novel treatment options. The use of oncolytic viruses as potential therapeutics has been researched for some time. Zika virus (ZIKV) has demonstrated oncotropism and oncolytic effects on GBM stem cells (GSCs). To address the need for safe and effective GBM treatments, we designed an attenuated ZIKV strain (ZOL-1) that does not cause paralytic or neurological diseases in mouse models compared with unmodified ZIKV. Importantly, we found that patient-derived GBM tumors exhibited susceptibility (responders) and non-susceptibility (non-responders) to ZOL-1-mediated tumor cell killing, as evidenced by differential apoptotic cell death and cell viability upon ZOL-1 treatment. The oncolytic effect observed in responder cells was seen both in vitro in neurosphere models and in vivo upon xenograft. Finally, we observed that the use of ZOL-1 as combination therapy with multiple PI3K-AKT inhibitors in non-responder GBM resulted in enhanced chemotherapeutic efficacy. Altogether, this study establishes ZOL-1 as a safe and effective treatment against GBM and provides a foundation to conduct further studies evaluating its potential as an effective adjuvant with other chemotherapies and kinase inhibitors.
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影响因子：
2.9
作者：
De Wolf, Elizabeth;De Wolf, Christopher;Richardson, Alan
通讯作者：
Richardson, Alan
DOI：
10.1038/mt.2008.184
发表时间：
2008-11
期刊：
Molecular therapy : the journal of the American Society of Gene Therapy
影响因子：
--
作者：
Dobrikova EY;Broadt T;Poiley-Nelson J;Yang X;Soman G;Giardina S;Harris R;Gromeier M
通讯作者：
Gromeier M
影响因子：
6.1
作者：
Ghareghomi, Somayyeh;Ahmadian, Shahin;Hemmati, Salar
通讯作者：
Hemmati, Salar
影响因子：
1.1
作者：
Davis ME
通讯作者：
Davis ME
用寨卡病毒减毒活疫苗候选药物治疗人类胶质母细胞瘤。
影响因子：
6.4
作者：
Chen Q;Wu J;Ye Q;Ma F;Zhu Q;Wu Y;Shan C;Xie X;Li D;Zhan X;Li C;Li XF;Qin X;Zhao T;Wu H;Shi PY;Man J;Qin CF
通讯作者：
Qin CF