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

Mostaghel EA, Morgan A, Zhang X, Marck BT, Xia J, Hunter-Merrill R, Gulati R, Plymate S, Vessella RL, Corey E, Higano CS, Matsumoto AM, Montgomery RB, Nelson PS - PLoS ONE (2014)

Bottom Line: In LuCaP96 tumors (T:DHT 10:1), survival was not improved despite similar DHT reduction (0.02 ng/gm).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.

View Article: PubMed Central - PubMed

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.

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.

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Tumor growth and androgen levels in prostate cancer xenografts treated with castration and dutasteride.Mean tumor volumes in mice bearing LuCaP35 (A) and LuCaP96 (B) xenografts. Intact male SCID mice were subcutaneously implanted with 30 mm3 pieces of the indicated xenograft. When tumors reached ∼300mm3, mice were castrated and randomly enrolled into cohorts treated with either vehicle (Cx) or dutasteride (Cx+Dut) for 8 weeks (denoted by black line above x-axis). Mean tumor volumes are depicted for each treatment group at the indicated days post enrollment (Cx, black squares; Cx+Dut, white circles).
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pone-0111545-g002: Tumor growth and androgen levels in prostate cancer xenografts treated with castration and dutasteride.Mean tumor volumes in mice bearing LuCaP35 (A) and LuCaP96 (B) xenografts. Intact male SCID mice were subcutaneously implanted with 30 mm3 pieces of the indicated xenograft. When tumors reached ∼300mm3, mice were castrated and randomly enrolled into cohorts treated with either vehicle (Cx) or dutasteride (Cx+Dut) for 8 weeks (denoted by black line above x-axis). Mean tumor volumes are depicted for each treatment group at the indicated days post enrollment (Cx, black squares; Cx+Dut, white circles).

Mentions: Mean tumor volumes in LuCaP35 tumors were markedly suppressed by the combination of castration plus dutasteride vs. castration alone (Figure 2A). Tumor growth occurred in three distinct stages following initiation of treatment: a brief period of continued growth (days 0–14), a prolonged phase of tumor regression or stability (days 14–75), and a final phase of tumor re-growth (days 75–200). To better quantitate the impact of dutasteride, we compared tumor volume trajectories in castration vs. castration plus dutasteride groups using a linear mixed model applied to each post-treatment phase. Dutasteride plus castration significantly decreased the percent increase in tumor volume per day versus castration alone in the initial ‘on-treatment’ stage (from 3.2% [95%CI 2.7–3.7] to 0.9% [95%CI 0.2–2.0]; p<0.0001), and increased the percent of tumor regression per day in the subsequent phase (from 1.2% [95%CI 0.5–1.8] to 3.6% [95%CI 2.0–5.3]; p<0.0001). However, following discontinuation of therapy, dutasteride-treated tumors demonstrated more rapid percent re-growth per day (from 1.1% [95%CI 0.9–1.3] to 2.3% [95%CI 1.8–2.9]; p<0.0001), suggesting continued therapy would be required to maintain therapeutic efficacy.


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

Mostaghel EA, Morgan A, Zhang X, Marck BT, Xia J, Hunter-Merrill R, Gulati R, Plymate S, Vessella RL, Corey E, Higano CS, Matsumoto AM, Montgomery RB, Nelson PS - PLoS ONE (2014)

Tumor growth and androgen levels in prostate cancer xenografts treated with castration and dutasteride.Mean tumor volumes in mice bearing LuCaP35 (A) and LuCaP96 (B) xenografts. Intact male SCID mice were subcutaneously implanted with 30 mm3 pieces of the indicated xenograft. When tumors reached ∼300mm3, mice were castrated and randomly enrolled into cohorts treated with either vehicle (Cx) or dutasteride (Cx+Dut) for 8 weeks (denoted by black line above x-axis). Mean tumor volumes are depicted for each treatment group at the indicated days post enrollment (Cx, black squares; Cx+Dut, white circles).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214744&req=5

pone-0111545-g002: Tumor growth and androgen levels in prostate cancer xenografts treated with castration and dutasteride.Mean tumor volumes in mice bearing LuCaP35 (A) and LuCaP96 (B) xenografts. Intact male SCID mice were subcutaneously implanted with 30 mm3 pieces of the indicated xenograft. When tumors reached ∼300mm3, mice were castrated and randomly enrolled into cohorts treated with either vehicle (Cx) or dutasteride (Cx+Dut) for 8 weeks (denoted by black line above x-axis). Mean tumor volumes are depicted for each treatment group at the indicated days post enrollment (Cx, black squares; Cx+Dut, white circles).
Mentions: Mean tumor volumes in LuCaP35 tumors were markedly suppressed by the combination of castration plus dutasteride vs. castration alone (Figure 2A). Tumor growth occurred in three distinct stages following initiation of treatment: a brief period of continued growth (days 0–14), a prolonged phase of tumor regression or stability (days 14–75), and a final phase of tumor re-growth (days 75–200). To better quantitate the impact of dutasteride, we compared tumor volume trajectories in castration vs. castration plus dutasteride groups using a linear mixed model applied to each post-treatment phase. Dutasteride plus castration significantly decreased the percent increase in tumor volume per day versus castration alone in the initial ‘on-treatment’ stage (from 3.2% [95%CI 2.7–3.7] to 0.9% [95%CI 0.2–2.0]; p<0.0001), and increased the percent of tumor regression per day in the subsequent phase (from 1.2% [95%CI 0.5–1.8] to 3.6% [95%CI 2.0–5.3]; p<0.0001). However, following discontinuation of therapy, dutasteride-treated tumors demonstrated more rapid percent re-growth per day (from 1.1% [95%CI 0.9–1.3] to 2.3% [95%CI 1.8–2.9]; p<0.0001), suggesting continued therapy would be required to maintain therapeutic efficacy.

Bottom Line: In LuCaP96 tumors (T:DHT 10:1), survival was not improved despite similar DHT reduction (0.02 ng/gm).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.

View Article: PubMed Central - PubMed

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.

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.

Show MeSH
Related in: MedlinePlus