Studebaker Adam W, Hutzen Brian J, Pierson Christopher R, Haworth Kellie B, Cripe Timothy P, Jackson Eric M, Leonard Jeffrey R
Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.
Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA.
Mol Ther Oncolytics. 2017 May 25;6:22-30. doi: 10.1016/j.omto.2017.05.005. eCollection 2017 Sep 15.
Pediatric brain tumors including medulloblastoma and atypical teratoid/rhabdoid tumor are associated with significant mortality and treatment-associated morbidity. While medulloblastoma tumors within molecular subgroups 3 and 4 have a propensity to metastasize, atypical teratoid/rhabdoid tumors frequently afflict a very young patient population. Adjuvant treatment options for children suffering with these tumors are not only sub-optimal but also associated with many neurocognitive obstacles. A potentially novel treatment approach is oncolytic virotherapy, a developing therapeutic platform currently in early-phase clinical trials for pediatric brain tumors and recently US Food and Drug Administration (FDA)-approved to treat melanoma in adults. We evaluated the therapeutic potential of the clinically available oncolytic herpes simplex vector rRp450 in cell lines derived from medulloblastoma and atypical teratoid/rhabdoid tumor. Cells of both tumor types were supportive of virus replication and virus-mediated cytotoxicity. Orthotopic xenograft models of medulloblastoma and atypical teratoid/rhabdoid tumors displayed significantly prolonged survival following a single, stereotactic intratumoral injection of rRp450. Furthermore, addition of the chemotherapeutic prodrug cyclophosphamide (CPA) enhanced rRp450's in vivo efficacy. In conclusion, oncolytic herpes viruses with the ability to bioactivate the prodrug CPA within the tumor microenvironment warrant further investigation as a potential therapy for pediatric brain tumors.
小儿脑肿瘤，包括髓母细胞瘤和非典型畸胎样/横纹肌样瘤，与显著的死亡率和治疗相关的发病率相关。虽然分子亚组3和4中的髓母细胞瘤有转移倾向，但非典型畸胎样/横纹肌样瘤经常困扰非常年幼的患者群体。患有这些肿瘤的儿童的辅助治疗选择不仅不理想，而且还存在许多神经认知障碍。一种潜在的新型治疗方法是溶瘤病毒疗法，这是一个正在发展的治疗平台，目前正处于小儿脑肿瘤的早期临床试验阶段，最近美国食品药品监督管理局（FDA）已批准其用于治疗成人黑色素瘤。我们评估了临床可用的溶瘤单纯疱疹病毒载体rRp450在源自髓母细胞瘤和非典型畸胎样/横纹肌样瘤的细胞系中的治疗潜力。两种肿瘤类型的细胞都支持病毒复制和病毒介导的细胞毒性。在髓母细胞瘤和非典型畸胎样/横纹肌样瘤的原位异种移植模型中，单次立体定向瘤内注射rRp450后生存期显著延长。此外，添加化疗前药环磷酰胺（CPA）可增强rRp450的体内疗效。总之，能够在肿瘤微环境中生物激活前药CPA的溶瘤疱疹病毒作为小儿脑肿瘤的潜在治疗方法值得进一步研究。
