Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression.
Enhanced Sensitivity of Patient-Derived Pediatric High-Grade Brain Tumor Xenografts to Oncolytic HSV-1 Virotherapy Correlates with Nectin-1 Expression.
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DOI：
10.1038/s41598-018-32353-x
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发表时间：
2018-09-17
影响因子：
4.6
通讯作者：
Markert JM
中科院分区：
文献类型：
--
作者：
Friedman GK;Bernstock JD;Chen D;Nan L;Moore BP;Kelly VM;Youngblood SL;Langford CP;Han X;Ring EK;Beierle EA;Gillespie GY;Markert JM
儿童高级别脑肿瘤和成人胶质母细胞瘤具有显著的发病率和死亡率。溶瘤性单纯疱疹病毒-1 （oHSV）是一种很有前途的靶向脑肿瘤的方法；oHSV G207和M032（编码人白细胞介素-12）目前分别在患有恶性幕上脑瘤的儿童和患有胶质母细胞瘤的成人中进行I期临床试验。我们试图比较患者来源的儿童恶性脑肿瘤和成人胶质母细胞瘤异种移植物对这些临床相关的oHSV的敏感性。在这样做的过程中，我们发现儿童脑肿瘤对病毒更敏感，并且比成人胶质母细胞瘤表达更多的连接素-1 （CD111）。与成人胶质母细胞瘤相比，小儿胚胎瘤和胶质瘤对M002的敏感性分别高出74倍和14倍，对G207的敏感性分别高出16倍和6倍。值得注意的是，儿童胚胎肿瘤比神经胶质肿瘤更敏感。敏感性的差异可能部分归因于连接素-1的表达，它预测了对病毒的反应。在儿童和成人颅内肿瘤异种移植模型中，oHSV治疗延长了生存期。我们的研究结果表明，儿童脑肿瘤是oHSV的理想靶点，脑肿瘤中nectin-1的表达可能是预测患者对oHSV反应的有用生物标志物。
Pediatric high-grade brain tumors and adult glioblastoma are associated with significant morbidity and mortality. Oncolytic herpes simplex virus-1 (oHSV) is a promising approach to target brain tumors; oHSV G207 and M032 (encodes human interleukin-12) are currently in phase I clinical trials in children with malignant supratentorial brain tumors and adults with glioblastoma, respectively. We sought to compare the sensitivity of patient-derived pediatric malignant brain tumor and adult glioblastoma xenografts to these clinically-relevant oHSV. In so doing we found that pediatric brain tumors were more sensitive to the viruses and expressed significantly more nectin-1 (CD111) than adult glioblastoma. Pediatric embryonal and glial tumors were 74-fold and 14-fold more sensitive to M002 and 16-fold and 6-fold more sensitive to G207 than adult glioblastoma, respectively. Of note, pediatric embryonal tumors were more sensitive than glial tumors. Differences in sensitivity may be due in part to nectin-1 expression, which predicted responses to the viruses. Treatment with oHSV resulted in prolonged survival in both pediatric and adult intracranial patient-dervied tumor xenograft models. Our results suggest that pediatric brain tumors are ideal targets for oHSV and that brain tumor expression of nectin-1 may be a useful biomarker to predict patient response to oHSV.
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DOI：
10.1038/mto.2014.10
发表时间：
2015
期刊：
Molecular therapy oncolytics
影响因子：
--
作者：
Leddon JL;Chen CY;Currier MA;Wang PY;Jung FA;Denton NL;Cripe KM;Haworth KB;Arnold MA;Gross AC;Eubank TD;Goins WF;Glorioso JC;Cohen JB;Grandi P;Hildeman DA;Cripe TP
通讯作者：
Cripe TP
影响因子：
21.3
作者：
Farassati, F;Yang, AD;Lee, PWK
通讯作者：
Lee, PWK
影响因子：
5.4
作者：
Krummenacher, C;Nicola, AV;Eisenberg, RJ
通讯作者：
Eisenberg, RJ
影响因子：
12.4
作者：
Markert, James M.;Razdan, Shantanu N.;Gillespie, G. Yancey
通讯作者：
Gillespie, G. Yancey
影响因子：
4.7
作者：
Friedman GK;Raborn J;Kelly VM;Cassady KA;Markert JM;Gillespie GY
通讯作者：
Gillespie GY