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PLoS One. 2014 Oct 30;9(10):e111545. doi: 10.1371/journal.pone.0111545. eCollection 2014.

Prostate cancer characteristics associated with response to pre-receptor targeting of the androgen axis.

Author information

1
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.
2
Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
3
Department of Urology, University of Washington School of Medicine, Seattle, Washington, United States of America.
4
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.
5
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
6
Department of Medicine, University of Washington School of Medicine, Seattle, Washington, United States of America.

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.

PMID:
25356728
PMCID:
PMC4214744
DOI:
10.1371/journal.pone.0111545
[Indexed for MEDLINE]
Free PMC Article

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