Tanimoto Terutaka, Tazawa Hiroshi, Ieda Takeshi, Nouso Hiroshi, Tani Morimichi, Oyama Takanori, Urata Yasuo, Kagawa Shunsuke, Noda Takuo, Fujiwara Toshiyoshi
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
Mol Ther Oncolytics. 2020 Jun 1;18:14-23. doi: 10.1016/j.omto.2020.05.015. eCollection 2020 Sep 25.
Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. High-risk NB is characterized by amplification and human telomerase reverse transcriptase () rearrangement, contributing to hTERT activation and a poor outcome. For targeting hTERT-activated tumors, we developed two oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in which the hTERT promoter drives expression of the viral gene for tumor-specific virus replication. In this study, we demonstrate the therapeutic potential of the hTERT-driven oncolytic adenoviruses OBP-301 and OBP-702 using four human MYCN-amplified NB cell lines (IMR-32, CHP-134, NB-1, LA-N-5) exhibiting high hTERT expression. OBP-301 and OBP-702 exhibited a strong antitumor effect in association with autophagy in NB cells. Virus-mediated activation of E2F1 protein suppressed MYCN expression. OBP-301 and OBP-702 significantly suppressed the growth of subcutaneous CHP-134 tumors. Thus, these hTERT-driven oncolytic adenoviruses are promising antitumor agents for eliminating MYCN-amplified NB cells via E2F1-mediated suppression of MYCN protein.
神经母细胞瘤（NB）是外周交感神经系统的原发性恶性肿瘤。高危NB的特征是扩增和人端粒酶逆转录酶（）重排，导致hTERT激活及预后不良。为了靶向hTERT激活的肿瘤，我们开发了两种溶瘤腺病毒，即OBP-301和携带肿瘤抑制因子p53的OBP-702，其中hTERT启动子驱动病毒基因表达以实现肿瘤特异性病毒复制。在本研究中，我们使用四种表现出高hTERT表达的人MYCN扩增NB细胞系（IMR-32、CHP-134、NB-1、LA-N-5），证明了hTERT驱动的溶瘤腺病毒OBP-301和OBP-702的治疗潜力。OBP-301和OBP-702在NB细胞中与自噬相关表现出强大的抗肿瘤作用。病毒介导的E2F1蛋白激活抑制了MYCN表达。OBP-301和OBP-702显著抑制了皮下CHP-134肿瘤的生长。因此，这些hTERT驱动的溶瘤腺病毒有望成为通过E2F1介导的MYCN蛋白抑制来消除MYCN扩增NB细胞的抗肿瘤药物。
