Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cells

Hideki Yoshida, Mizuho Sato-Dahlman, Praveensingh Hajeri, Kari Jacobsen, Lisa Koodie, Chikako Yanagiba, Ryan Shanley, Masato Yamamoto

Research output: Contribution to journalArticlepeer-review

Abstract

The PAX3-FOXO1 fusion gene functions as a transactivator and increases expression of many cancer-related genes. These lead to metastases and other unfavorable outcomes for alveolar rhabdomyosarcoma (ARMS) patients. In order to target ARMS with the PAX3-FOXO1 transactivator, we developed an Oncolytic Adenovirus (OAd) regulated by the myogenin (pMYOG) promoter with a mutation in the Myocyte Enhancer Factor-2 binding site (mMEF2) in this study. The expression of MYOG in the two RMS cell lines (Rh30; PAX3-FOXO1-positive, RD; PAX3-FOXO1-negative) is about 1,000 times higher than normal skeletal muscle cell (SkMC). Ad5/3-pMYOG(S)-mMEF2 (short-length pMYOG-controlled OAd with mMEF2) showed strong replication and cytocidal effect in Rh30, but to a much lesser extent in RD. Ad5/3-pMYOG(S) (pMYOG-controlled OAd with native pMYOG) showed similar effects in RD and Rh30. Neither virus killed SkMC, indicating that Ad5/3-pMYOG(S)-mMEF2 selectively replicates and kills cells with PAX3-FOXO1. Additionally, Ad5/3-pMYOG(S)-mMEF2 showed replication and spread in vitro as well as tumor growth suppression and intratumoral viral spread in vivo, selectively in Rh30 not in RD. Our findings revealed that Ad5/3-pMYOG(S)-mMEF2 shows a promise as a safe and potent therapy to improve treatment in PAX3-FOXO1-positive ARMSs.

Original languageEnglish (US)
Article number100997
JournalTranslational Oncology
Volume14
Issue number2
DOIs
StatePublished - Feb 2021

Bibliographical note

Funding Information:
This research was supported by grants from Grant from Karen Wyckoff Rein in Sarcoma Foundation and NIH/NCI : R01CA228760 , R01CA196215 , R01CA168448 (to M. Yamamoto). The funding was used to support all study design, data analyses, and manuscript constructions.

Funding Information:
Financial support: Partly supported by the Karen Wyckoff Rein in Sarcoma Foundation, and NIH/NCI: R01CA228760, R01CA196215, R01CA168448

Publisher Copyright:
© 2020 The Authors

Keywords

  • Child cancer
  • Fusion-gene
  • MEF2
  • Soft-tissue sarcoma
  • Virotherapy

PubMed: MeSH publication types

  • Journal Article

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