Androgen receptor attenuation of Ad5 replication: Implications for the development of conditionally replication competent adenoviruses

Naseruddin Höti; Ying Li; Chien Lun Chen; Wasim H. Chowdhury; David C. Johns; Qinghua Xia; Arup Kabul; Jer Tsong Hsieh; Michael Berg; Gary Ketner; Shawn E. Lupold; Ronald Rodriguez

doi:10.1038/sj.mt.6300223

Androgen receptor attenuation of Ad5 replication: Implications for the development of conditionally replication competent adenoviruses

Naseruddin Höti, Ying Li, Chien Lun Chen, Wasim H. Chowdhury, David C. Johns, Qinghua Xia, Arup Kabul, Jer Tsong Hsieh, Michael Berg, Gary Ketner, Shawn E. Lupold, Ronald Rodriguez

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

Conditionally replication competent adenoviruses (CRAds) represent one of the most intensely studied gene therapy strategies for a variety of malignancies, including prostate cancer. These viruses can be generated by placing a tissue or cancer-specific promoter upstream of one or more of the viral genes required for replication (e.g., E1A, E1B). We report here that E1A inhibits androgen receptor (AR) target gene induction and, correspondingly, activated AR inhibits adenoviral replication. This mutual inhibition appears to be an indirect effect, possibly through competition for shared transcriptional co-activators. The net effect is that the oncolytic effect of prostate-specific CRAds is attenuated by these interactions. Fusion of the E1A to AR ameliorates this inhibition, while enhancing specificity. These findings have significant implications in the development of prostate-specific CRAd therapies.

Original language	English (US)
Pages (from-to)	1495-1503
Number of pages	9
Journal	Molecular Therapy
Volume	15
Issue number	8
DOIs	https://doi.org/10.1038/sj.mt.6300223
State	Published - Aug 2007

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

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title = "Androgen receptor attenuation of Ad5 replication: Implications for the development of conditionally replication competent adenoviruses",

abstract = "Conditionally replication competent adenoviruses (CRAds) represent one of the most intensely studied gene therapy strategies for a variety of malignancies, including prostate cancer. These viruses can be generated by placing a tissue or cancer-specific promoter upstream of one or more of the viral genes required for replication (e.g., E1A, E1B). We report here that E1A inhibits androgen receptor (AR) target gene induction and, correspondingly, activated AR inhibits adenoviral replication. This mutual inhibition appears to be an indirect effect, possibly through competition for shared transcriptional co-activators. The net effect is that the oncolytic effect of prostate-specific CRAds is attenuated by these interactions. Fusion of the E1A to AR ameliorates this inhibition, while enhancing specificity. These findings have significant implications in the development of prostate-specific CRAd therapies.",

author = "Naseruddin H{\"o}ti and Ying Li and Chen, {Chien Lun} and Chowdhury, {Wasim H.} and Johns, {David C.} and Qinghua Xia and Arup Kabul and Hsieh, {Jer Tsong} and Michael Berg and Gary Ketner and Lupold, {Shawn E.} and Ronald Rodriguez",

note = "Funding Information: The authors would like to thank the following people for helpful discussions and advice during the course of these studies: William Isaacs (Department of Urology, Johns Hopkins School of Medicine), Theodore DeWeese (Department of Radiation Oncology, Johns Hopkins School of Medicine), Donald S. Coffey (Department of Urology, Johns Hopkins School of Medicine), William G. Nelson (Department of Oncology, Johns Hopkins School of Medicine), and Drew Pardoll (Department of Oncology, Johns Hopkins School of Medicine). This study was supported in part by grants from NIH 2T32DK07552 and 2P50CA58236-09A1, under Award Number DAMD17-03-2-0033, by the Department of Defense Prostate Cancer Research Program, which is managed by the U.S. Army Medical Research and Material Command, and by awards from the Prostate Cancer Foundation, and Maren Foundation.",

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AU - Johns, David C.

AU - Xia, Qinghua

AU - Kabul, Arup

AU - Hsieh, Jer Tsong

AU - Berg, Michael

AU - Ketner, Gary

AU - Lupold, Shawn E.

AU - Rodriguez, Ronald

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Androgen receptor attenuation of Ad5 replication: Implications for the development of conditionally replication competent adenoviruses

Abstract

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