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.
authors.affiliation: James Brady Urological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: T J
authors.initials: TJ
authors.lastname: Johnson
authors.forename: N
authors.initials: N
authors.lastname: Höti
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: W H
authors.initials: WH
authors.lastname: Chowdhury
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: S E
authors.initials: SE
authors.lastname: Lupold
authors.forename: T
authors.initials: T
authors.lastname: Deweese
authors.forename: R
authors.initials: R
authors.lastname: Rodriguez
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D019943:Amino Acid Substitution; D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000528:radiation effects; D003131:Combined Modality Therapy; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000494:pharmacology*; D050130:Oncolytic Virotherapy; D050504:Oncolytic Viruses / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000628:therapy*; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics; D014105:Tosyl Compounds / Q000494:pharmacology*; D014759:Viral Envelope Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects / Q000528:radiation effects
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D014759:Viral Envelope Proteins; C053541:bicalutamide