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

Translational Oncology (Feb 2021)

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

Affiliations

Hideki Yoshida: Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States
Mizuho Sato-Dahlman: Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States
Praveensingh Hajeri: Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States
Kari Jacobsen: Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States
Lisa Koodie: Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States
Chikako Yanagiba: Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States
Ryan Shanley: Masonic Cancer Center, Biostatistics Core, University of Minnesota, Minneapolis, MN 55455, United States
Masato Yamamoto: Department of Surgery, University of Minnesota, Moos Tower 11-216, MMC195, 515 Delaware St SE, Minneapolis, MN 55455, United States; Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, United States; Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, United States; Corresponding author.

Journal volume & issue: Vol. 14, no. 2
p. 100997

Abstract

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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.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

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