Vazaios Konstantinos, Stavrakaki Εftychia, Vogelezang Lisette B, Ju Jie, Waranecki Piotr, Metselaar Dennis S, Meel Michaël H, Kemp Vera, van den Hoogen Bernadette G, Hoeben Rob C, Chiocca E Antonio, Goins William F, Stubbs Andrew, Li Yunlei, Alonso Marta M, Calkoen Friso G, Hulleman Esther, van der Lugt Jasper, Lamfers Martine L M
Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, the Netherlands.
Department of Neurosurgery, Brain Tumor Center, Erasmus Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands.
Mol Ther Oncol. 2024 Apr 15;32(2):200804. doi: 10.1016/j.omton.2024.200804. eCollection 2024 Jun 20.
Despite decades of research, the prognosis of high-grade pediatric brain tumors (PBTs) remains dismal; however, recent cases of favorable clinical responses were documented in clinical trials using oncolytic viruses (OVs). In the current study, we employed four different species of OVs: adenovirus Delta24-RGD, herpes simplex virus rQNestin34.5v1, reovirus R124, and the non-virulent Newcastle disease virus rNDV-F0-GFP against three entities of PBTs (high-grade gliomas, atypical teratoid/rhabdoid tumors, and ependymomas) to determine their efficacy. These four OVs were screened on 14 patient-derived PBT cell cultures and the degree of oncolysis was assessed using an ATP-based assay. Subsequently, the observed viral efficacies were correlated to whole transcriptome data and Gene Ontology analysis was performed. Although no significant tumor type-specific OV efficacy was observed, the analysis revealed the intrinsic biological processes that associated with OV efficacy. The predictive power of the identified expression profiles was further validated by screening additional PBTs. In summary, our results demonstrate OV susceptibility of multiple patient-derived PBT entities and the ability to predict responses to OVs using unique expression profiles. Such profiles may hold promise for future OV preselection with effective oncolytic potency in a specific tumor, therewith potentially improving OV responses.
尽管经过了数十年的研究，高级别儿童脑肿瘤（PBTs）的预后仍然不容乐观；然而，最近在使用溶瘤病毒（OVs）的临床试验中记录了一些临床反应良好的病例。在本研究中，我们使用了四种不同的溶瘤病毒：腺病毒Delta24-RGD、单纯疱疹病毒rQNestin34.5v1、呼肠孤病毒R124和无毒新城疫病毒rNDV-F0-GFP，针对三种儿童脑肿瘤实体（高级别胶质瘤、非典型畸胎样/横纹肌样肿瘤和室管膜瘤）来确定它们的疗效。这四种溶瘤病毒在14种源自患者的儿童脑肿瘤细胞培养物上进行了筛选，并使用基于ATP的检测方法评估了溶瘤程度。随后，将观察到的病毒疗效与全转录组数据相关联，并进行了基因本体分析。虽然未观察到明显的肿瘤类型特异性溶瘤病毒疗效，但分析揭示了与溶瘤病毒疗效相关的内在生物学过程。通过筛选更多的儿童脑肿瘤，进一步验证了所确定的表达谱的预测能力。总之，我们的结果证明了多种源自患者的儿童脑肿瘤实体对溶瘤病毒的敏感性，以及使用独特的表达谱预测对溶瘤病毒反应的能力。这些表达谱可能为未来在特定肿瘤中进行具有有效溶瘤效力的溶瘤病毒预选带来希望，从而有可能改善溶瘤病毒的反应。
