title: Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer.
abstract: Androgen deprivation therapy (ADT) remains the primary treatment for advanced prostate cancer. The efficacy of ADT has not been rigorously evaluated by demonstrating suppression of prostatic androgen activity at the target tissue and molecular level. We determined the efficacy and consistency of medical castration in suppressing prostatic androgen levels and androgen-regulated gene expression. Androgen levels and androgen-regulated gene expression (by microarray profiling, quantitative reverse transcription-PCR, and immunohistochemistry) were measured in prostate samples from a clinical trial of short-term castration (1 month) using the gonadotropin-releasing hormone antagonist, Acyline, versus placebo in healthy men. To assess the effects of long-term ADT, gene expression measurements were evaluated at baseline and after 3, 6, and 9 months of neoadjuvant ADT in prostatectomy samples from men with localized prostate cancer. Medical castration reduced tissue androgens by 75% and reduced the expression of several androgen-regulated genes (NDRG1, FKBP5, and TMPRSS2). However, many androgen-responsive genes, including the androgen receptor (AR) and prostate-specific antigen (PSA), were not suppressed after short-term castration or after 9 months of neoadjuvant ADT. Significant heterogeneity in PSA and AR protein expression was observed in prostate cancer samples at each time point of ADT. Medical castration based on serum testosterone levels cannot be equated with androgen ablation in the prostate microenvironment. Standard androgen deprivation does not consistently suppress androgen-dependent gene expression. Suboptimal suppression of tumoral androgen activity may lead to adaptive cellular changes allowing prostate cancer cell survival in a low androgen environment. Optimal clinical efficacy will require testing of novel approaches targeting complete suppression of systemic and intracrine contributions to the prostatic androgen microenvironment.
authors.affiliation: Fred Hutchinson Cancer Research Center, Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA.
authors.forename: Elahe A
authors.initials: EA
authors.lastname: Mostaghel
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Page
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Lin
authors.forename: Ladan
authors.initials: L
authors.lastname: Fazli
authors.forename: Ilsa M
authors.initials: IM
authors.lastname: Coleman
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: True
authors.forename: Beatrice
authors.initials: B
authors.lastname: Knudsen
authors.forename: David L
authors.initials: DL
authors.lastname: Hess
authors.forename: Colleen C
authors.initials: CC
authors.lastname: Nelson
authors.forename: Alvin M
authors.initials: AM
authors.lastname: Matsumoto
authors.forename: William J
authors.initials: WJ
authors.lastname: Bremner
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gleave
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
mesh_terms: D000328:Adult; D000728:Androgens / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D007987:Gonadotropin-Releasing Hormone / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D020411:Oligonucleotide Array Sequence Analysis; D009842:Oligopeptides / Q000627:therapeutic use; D009919:Orchiectomy / Q000379:methods; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013739:Testosterone / Q000037:antagonists & inhibitors* / Q000097:blood
chemical_list: D000728:Androgens; D009842:Oligopeptides; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D017430:Prostate-Specific Antigen; C109238:acyline