title: Targeted androgen pathway suppression in localized prostate cancer: a pilot study.
abstract: OBJECTIVE
  Ligand-mediated activation of the androgen receptor (AR) is critical for prostate cancer (PCa) survival and proliferation. The failure to completely ablate tissue androgens may limit suppression of PCa growth. We evaluated combinations of CYP17A and 5-α-reductase inhibitors for reducing prostate androgen levels, AR signaling, and PCa volumes.
  
  
  METHODS
  Thirty-five men with intermediate/high-risk clinically localized PCa were randomly assigned to goserelin combined with dutasteride (ZD), bicalutamide and dutasteride (ZBD), or bicalutamide, dutasteride, and ketoconazole (ZBDK) for 3 months before prostatectomy. Controls included patients receiving combined androgen blockade with luteinizing hormone-releasing hormone agonist and bicalutamide. The primary outcome measure was tissue dihydrotestosterone (DHT) concentration.
  
  
  RESULTS
  Prostate DHT levels were substantially lower in all experimental arms (0.02 to 0.04 ng/g v 0.92 ng/g in controls; P < .001). The ZBDK group demonstrated the greatest percentage decline in serum testosterone, androsterone, and dehydroepiandrosterone sulfate (P < .05 for all). Staining for AR and the androgen-regulated genes prostate-specific antigen and TMPRSS2 was strongly suppressed in benign glands and moderately in malignant glands (P < .05 for all). Two patients had pathologic complete response, and nine had ≤ 0.2 cm(3) of residual tumor (defined as a near-complete response), with the largest numbers of complete and near-complete responses in the ZBDK group.
  
  
  CONCLUSIONS
  Addition of androgen synthesis inhibitors lowers prostate androgens below that achieved with standard therapy, but significant AR signaling remains. Tissue-based analysis of steroids and AR signaling is critical to informing the search for optimal local and systemic control of high-risk prostate cancer.
authors: Elahe A. Mostaghel, Rachel Hunter Merrill, and Roman Gulati, Fred Hutchinson Cancer Research Center; Elahe A. Mostaghel, Peter S. Nelson, Paul Lange, Daniel W. Lin, William Ellis, Robert Vessella, and Bruce Montgomery, University of Washington; Brett Marck, Alvin M. Matsumoto, and Lawrence D. True, Veterans Affairs Puget Sound Health Care System, Seattle, WA; Mary Ellen Taplin and Philip Kantoff, Dana-Farber Cancer Institute, Harvard Medical School; Steven Balk, Beth Israel Deaconess Medical Center, Boston, MA; and Daniel Tamae and Trevor Penning, University of Pennsylvania, Philadelphia, PA.
authors: Elahe A
authors: EA
authors: Mostaghel
authors: Peter S
authors: PS
authors: Nelson
authors: Paul
authors: P
authors: Lange
authors: Daniel W
authors: DW
authors: Lin
authors: Mary Ellen
authors: ME
authors: Taplin
authors: Steven
authors: S
authors: Balk
authors: William
authors: W
authors: Ellis
authors: Philip
authors: P
authors: Kantoff
authors: Brett
authors: B
authors: Marck
authors: Daniel
authors: D
authors: Tamae
authors: Alvin M
authors: AM
authors: Matsumoto
authors: Lawrence D
authors: LD
authors: True
authors: Robert
authors: R
authors: Vessella
authors: Trevor
authors: T
authors: Penning
authors: Rachel
authors: R
authors: Hunter Merrill
authors: Roman
authors: R
authors: Gulati
authors: Bruce
authors: B
authors: Montgomery
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000008:administration & dosage; D000368:Aged; D000369:Aged, 80 and over; D000726:Androgen Antagonists / Q000627:therapeutic use*; D059002:Androgen Receptor Antagonists / Q000627:therapeutic use*; D000738:Androsterone / Q000097:blood; D000813:Anilides / Q000008:administration & dosage; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001378:Azasteroids / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000378:metabolism*; D017024:Chemotherapy, Adjuvant; D013196:Dihydrotestosterone / Q000097:blood / Q000378:metabolism; D000068538:Dutasteride; D017273:Goserelin / Q000008:administration & dosage; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D020360:Neoadjuvant Therapy / Q000379:methods; D009367:Neoplasm Staging; D009570:Nitriles / Q000008:administration & dosage; D010865:Pilot Projects; D011467:Prostate / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D013739:Testosterone / Q000097:blood; D014105:Tosyl Compounds / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D001378:Azasteroids; D014408:Biomarkers, Tumor; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; D017273:Goserelin; D013739:Testosterone; C053541:bicalutamide; D000738:Androsterone; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D017430:Prostate-Specific Antigen; D000068538:Dutasteride; D007654:Ketoconazole