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

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

doi:10.1016/j.tranon.2020.100997

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

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

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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 language	English (US)
Article number	100997
Journal	Translational Oncology
Volume	14
Issue number	2
DOIs	https://doi.org/10.1016/j.tranon.2020.100997
State	Published - Feb 1 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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.tranon.2020.100997

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title = "Mutant myogenin promoter-controlled oncolytic adenovirus selectively kills PAX3-FOXO1-positive rhabdomyosarcoma cells",

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.",

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author = "Hideki Yoshida and Mizuho Sato-Dahlman and Praveensingh Hajeri and Jacobsen, {Kari L} and Lisa Koodie and Chikako Yanagiba and Ryan Shanley and Masato Yamamoto",

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: {\textcopyright} 2020 The Authors",

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AU - Yoshida, Hideki

AU - Sato-Dahlman, Mizuho

AU - Hajeri, Praveensingh

AU - Jacobsen, Kari L

AU - Koodie, Lisa

AU - Yanagiba, Chikako

AU - Shanley, Ryan

AU - Yamamoto, Masato

N1 - 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

PY - 2021/2/1

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N2 - 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.

AB - 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.

KW - Child cancer

KW - Fusion-gene

KW - MEF2

KW - Soft-tissue sarcoma

KW - Virotherapy

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ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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