Elimination of MYCN-Amplified Neuroblastoma Cells by Telomerase-Targeted Oncolytic Virus via MYCN Suppression

Terutaka Tanimoto; Hiroshi Tazawa; Takeshi Ieda; Hiroshi Nouso; Morimichi Tani; Takanori Oyama; Yasuo Urata; Shunsuke Kagawa; Takuo Noda; Toshiyoshi Fujiwara

doi:10.1016/j.omto.2020.05.015

Elimination of MYCN-Amplified Neuroblastoma Cells by Telomerase-Targeted Oncolytic Virus via MYCN Suppression

Mol Ther Oncolytics. 2020 Jun 1:18:14-23. doi: 10.1016/j.omto.2020.05.015. eCollection 2020 Sep 25.

Authors

Terutaka Tanimoto^{1

2}, Hiroshi Tazawa^{1

3}, Takeshi Ieda¹, Hiroshi Nouso², Morimichi Tani², Takanori Oyama², Yasuo Urata⁴, Shunsuke Kagawa^{1

5}, Takuo Noda², Toshiyoshi Fujiwara¹

Affiliations

¹ Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
² Department of Pediatric Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan.
³ Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700-8558, Japan.
⁴ Oncolys BioPharma, Inc., Tokyo 106-0032, Japan.
⁵ Minimally Invasive Therapy Center, Okayama University Hospital, Okayama 700-8558, Japan.

Abstract

Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. High-risk NB is characterized by MYCN amplification and human telomerase reverse transcriptase (hTERT) 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 E1 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.

Keywords: E2F1; MYCN; adenovirus; hTERT; neuroblastoma.