Bicalutamide-activated oncolytic adenovirus for the adjuvant therapy of high-risk prostate cancer

T. J. Johnson, N. Höti, C. Liu, W. H. Chowdhury, Y. Li, Y. Zhang, S. E. Lupold, T. Deweese, Ronald Rodriguez

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Conditionally replicating adenoviruses (CRAds) utilize tissue-specific promoters to control the expression of the early genes, E1A and E1B, to preferentially replicate and lyse tumor cells (oncolysis). Previous CRAds used in prostate cancer (PCa) gene therapy require androgens to activate prostate-specific promoters and induce viral replication. Unfortunately, these CRAds have reduced activity in patients on androgen-suppressive therapy. We describe a novel prostate-specific CRAd generated by fusing the E1A gene to the androgen receptor (AR) cDNA with a point mutation in codon 685 (C685Y). The E1A-AR fusion neutralizes the previously described mutual inhibition of E1A and AR, and the C685Y point mutation alters specificity of steroid ligand binding to the AR, such that both androgens and nonsteroidal anti-androgens can activate viral replication. We demonstrate that the mutated E1A-AR retained the ability to function in regulating AR-responsive genes and E1A-responsive viral genes. In combination therapy of virus, bicalutamide (anti-androgen) and radiation, a profound impact on cell death by viral oncolysis was seen both in vitro and tumor xenografts. To our knowledge, this is the first gene therapy engineered to be enhanced by anti-androgens and a particularly attractive adjuvant strategy for intensity-modulated radiation therapy of high-risk PCas.

Original languageEnglish (US)
Pages (from-to)394-402
Number of pages9
JournalCancer Gene Therapy
Volume20
Issue number7
DOIs
StatePublished - Jul 2013

Fingerprint

Androgen Receptors
Adenoviridae
Prostatic Neoplasms
Androgens
Point Mutation
Genetic Therapy
Prostate
Therapeutics
Nonsteroidal Anti-Androgens
Viral Genes
Neoplasm Genes
Heterografts
Codon
Genes
bicalutamide
Neoplasms
Cell Death
Radiotherapy
Complementary DNA
Steroids

Keywords

  • Adenovirus
  • Anti-androgen
  • CRAd
  • E1A-AR
  • Fiber-IRES-GFP
  • Radiation

ASJC Scopus subject areas

  • Cancer Research
  • Molecular Medicine
  • Molecular Biology

Cite this

Bicalutamide-activated oncolytic adenovirus for the adjuvant therapy of high-risk prostate cancer. / Johnson, T. J.; Höti, N.; Liu, C.; Chowdhury, W. H.; Li, Y.; Zhang, Y.; Lupold, S. E.; Deweese, T.; Rodriguez, Ronald.

In: Cancer Gene Therapy, Vol. 20, No. 7, 07.2013, p. 394-402.

Research output: Contribution to journalArticle

Johnson, TJ, Höti, N, Liu, C, Chowdhury, WH, Li, Y, Zhang, Y, Lupold, SE, Deweese, T & Rodriguez, R 2013, 'Bicalutamide-activated oncolytic adenovirus for the adjuvant therapy of high-risk prostate cancer', Cancer Gene Therapy, vol. 20, no. 7, pp. 394-402. https://doi.org/10.1038/cgt.2013.34
Johnson, T. J. ; Höti, N. ; Liu, C. ; Chowdhury, W. H. ; Li, Y. ; Zhang, Y. ; Lupold, S. E. ; Deweese, T. ; Rodriguez, Ronald. / Bicalutamide-activated oncolytic adenovirus for the adjuvant therapy of high-risk prostate cancer. In: Cancer Gene Therapy. 2013 ; Vol. 20, No. 7. pp. 394-402.
@article{db69eb31dbba40f3ab81e0b8f7532d95,
title = "Bicalutamide-activated oncolytic adenovirus for the adjuvant therapy of high-risk prostate cancer",
abstract = "Conditionally replicating adenoviruses (CRAds) utilize tissue-specific promoters to control the expression of the early genes, E1A and E1B, to preferentially replicate and lyse tumor cells (oncolysis). Previous CRAds used in prostate cancer (PCa) gene therapy require androgens to activate prostate-specific promoters and induce viral replication. Unfortunately, these CRAds have reduced activity in patients on androgen-suppressive therapy. We describe a novel prostate-specific CRAd generated by fusing the E1A gene to the androgen receptor (AR) cDNA with a point mutation in codon 685 (C685Y). The E1A-AR fusion neutralizes the previously described mutual inhibition of E1A and AR, and the C685Y point mutation alters specificity of steroid ligand binding to the AR, such that both androgens and nonsteroidal anti-androgens can activate viral replication. We demonstrate that the mutated E1A-AR retained the ability to function in regulating AR-responsive genes and E1A-responsive viral genes. In combination therapy of virus, bicalutamide (anti-androgen) and radiation, a profound impact on cell death by viral oncolysis was seen both in vitro and tumor xenografts. To our knowledge, this is the first gene therapy engineered to be enhanced by anti-androgens and a particularly attractive adjuvant strategy for intensity-modulated radiation therapy of high-risk PCas.",
keywords = "Adenovirus, Anti-androgen, CRAd, E1A-AR, Fiber-IRES-GFP, Radiation",
author = "Johnson, {T. J.} and N. H{\"o}ti and C. Liu and Chowdhury, {W. H.} and Y. Li and Y. Zhang and Lupold, {S. E.} and T. Deweese and Ronald Rodriguez",
year = "2013",
month = "7",
doi = "10.1038/cgt.2013.34",
language = "English (US)",
volume = "20",
pages = "394--402",
journal = "Cancer Gene Therapy",
issn = "0929-1903",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Bicalutamide-activated oncolytic adenovirus for the adjuvant therapy of high-risk prostate cancer

AU - Johnson, T. J.

AU - Höti, N.

AU - Liu, C.

AU - Chowdhury, W. H.

AU - Li, Y.

AU - Zhang, Y.

AU - Lupold, S. E.

AU - Deweese, T.

AU - Rodriguez, Ronald

PY - 2013/7

Y1 - 2013/7

N2 - Conditionally replicating adenoviruses (CRAds) utilize tissue-specific promoters to control the expression of the early genes, E1A and E1B, to preferentially replicate and lyse tumor cells (oncolysis). Previous CRAds used in prostate cancer (PCa) gene therapy require androgens to activate prostate-specific promoters and induce viral replication. Unfortunately, these CRAds have reduced activity in patients on androgen-suppressive therapy. We describe a novel prostate-specific CRAd generated by fusing the E1A gene to the androgen receptor (AR) cDNA with a point mutation in codon 685 (C685Y). The E1A-AR fusion neutralizes the previously described mutual inhibition of E1A and AR, and the C685Y point mutation alters specificity of steroid ligand binding to the AR, such that both androgens and nonsteroidal anti-androgens can activate viral replication. We demonstrate that the mutated E1A-AR retained the ability to function in regulating AR-responsive genes and E1A-responsive viral genes. In combination therapy of virus, bicalutamide (anti-androgen) and radiation, a profound impact on cell death by viral oncolysis was seen both in vitro and tumor xenografts. To our knowledge, this is the first gene therapy engineered to be enhanced by anti-androgens and a particularly attractive adjuvant strategy for intensity-modulated radiation therapy of high-risk PCas.

AB - Conditionally replicating adenoviruses (CRAds) utilize tissue-specific promoters to control the expression of the early genes, E1A and E1B, to preferentially replicate and lyse tumor cells (oncolysis). Previous CRAds used in prostate cancer (PCa) gene therapy require androgens to activate prostate-specific promoters and induce viral replication. Unfortunately, these CRAds have reduced activity in patients on androgen-suppressive therapy. We describe a novel prostate-specific CRAd generated by fusing the E1A gene to the androgen receptor (AR) cDNA with a point mutation in codon 685 (C685Y). The E1A-AR fusion neutralizes the previously described mutual inhibition of E1A and AR, and the C685Y point mutation alters specificity of steroid ligand binding to the AR, such that both androgens and nonsteroidal anti-androgens can activate viral replication. We demonstrate that the mutated E1A-AR retained the ability to function in regulating AR-responsive genes and E1A-responsive viral genes. In combination therapy of virus, bicalutamide (anti-androgen) and radiation, a profound impact on cell death by viral oncolysis was seen both in vitro and tumor xenografts. To our knowledge, this is the first gene therapy engineered to be enhanced by anti-androgens and a particularly attractive adjuvant strategy for intensity-modulated radiation therapy of high-risk PCas.

KW - Adenovirus

KW - Anti-androgen

KW - CRAd

KW - E1A-AR

KW - Fiber-IRES-GFP

KW - Radiation

UR - http://www.scopus.com/inward/record.url?scp=84880922001&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880922001&partnerID=8YFLogxK

U2 - 10.1038/cgt.2013.34

DO - 10.1038/cgt.2013.34

M3 - Article

C2 - 23764901

AN - SCOPUS:84880922001

VL - 20

SP - 394

EP - 402

JO - Cancer Gene Therapy

JF - Cancer Gene Therapy

SN - 0929-1903

IS - 7

ER -