title: Prostate cancer characteristics associated with response to pre-receptor targeting of the androgen axis.
abstract: BACKGROUND
  Factors influencing differential responses of prostate tumors to androgen receptor (AR) axis-directed therapeutics are poorly understood, and predictors of treatment efficacy are needed. We hypothesized that the efficacy of inhibiting DHT ligand synthesis would associate with intra-tumoral androgen ratios indicative of relative dependence on DHT-mediated growth.
  
  
  METHODS
  We characterized two androgen-sensitive prostate cancer xenograft models after androgen suppression by castration in combination with the SRD5A inhibitor, dutasteride, as well as a panel of castration resistant metastases obtained via rapid autopsy.
  
  
  RESULTS
  In LuCaP35 tumors (intra-tumoral T:DHT ratio 2:1) dutasteride suppressed DHT to 0.02 ng/gm and prolonged survival vs. castration alone (337 vs.152 days, HR 2.8, p = 0.0015). In LuCaP96 tumors (T:DHT 10:1), survival was not improved despite similar DHT reduction (0.02 ng/gm). LuCaP35 demonstrated higher expression of steroid biosynthetic enzymes maintaining DHT levels (5-fold higher SRD5A1, 41 fold higher, 99-fold higher RL-HSD, p<0.0001 for both), reconstitution of intra-tumoral DHT (to ∼30% of untreated tumors), and ∼2 fold increased expression of full length AR. In contrast, LuCaP96 demonstrated higher levels of steroid catabolizing enzymes (6.9-fold higher AKR1C2, 3000-fold higher UGT2B15, p = 0.002 and p<0.0001 respectively), persistent suppression of intra-tumoral DHT, and 6-8 fold induction of full length AR and the ligand independent V7 AR splice variant. Human metastases demonstrated bio-active androgen levels and AR full length and AR splice-variant expression consistent with the range observed in xenografts.
  
  
  CONCLUSIONS
  Intrinsic differences in basal steroidogenesis, as well as variable expression of full length and splice-variant AR, associate with response and resistance to pre-receptor AR ligand suppression. Expression of steroidogenic enzymes and AR isoforms may serve as potential biomarkers of sensitivity to potent AR-axis inhibition and should be validated in additional models.
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Elahe A
authors.initials: EA
authors.lastname: Mostaghel
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Morgan
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Xiaotun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America; Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington, United States of America.
authors.forename: Brett T
authors.initials: BT
authors.lastname: Marck
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Jing
authors.initials: J
authors.lastname: Xia
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Rachel
authors.initials: R
authors.lastname: Hunter-Merrill
authors.affiliation: Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
authors.forename: Roman
authors.initials: R
authors.lastname: Gulati
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America; Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Plymate
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Vessella
authors.affiliation: Department of Urology, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Eva
authors.initials: E
authors.lastname: Corey
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America; Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, Seattle, Washington, United States of America.
authors.forename: Alvin M
authors.initials: AM
authors.lastname: Matsumoto
authors.affiliation: Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Montgomery
authors.affiliation: Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America; Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Nelson
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D002369:Castration; D045744:Cell Line, Tumor; D018450:Disease Progression; D000068538:Dutasteride / Q000494:pharmacology / Q000627:therapeutic use; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000473:pathology; D020033:Protein Isoforms / Q000378:metabolism; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D011944:Receptors, Androgen / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D000728:Androgens; D008565:Membrane Proteins; D020033:Protein Isoforms; D011944:Receptors, Androgen; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase; C548467:SRD5A1 protein, human; D000068538:Dutasteride