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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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Response to dutasteride by tumor size at enrollment in LuCaP35 xenografts.Kaplan-Meier plots of progression free survival (defined as tumor size <750 mm3) in all LuCaP35 tumors treated with castration alone (Cx) vs. castration + dutasteride (Cx + Dut) (A), and in tumors enrolled into treatment when tumors were <250 mm3 (B). P-values for curve comparisons were generated using the Mantel-Haenszel logrank test. Mean tumor volume growth curves at the indicated days post enrollment in LuCaP35 tumors enrolled into treatment when tumors were <250 mm3 (C), between 250–400 mm3 (D), and >400 mm3 (E). Dutasteride treatment was continued for 8 weeks (denoted by black line above x-axis) in the castration + dutasteride group.
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pone-0111545-g003: Response to dutasteride by tumor size at enrollment in LuCaP35 xenografts.Kaplan-Meier plots of progression free survival (defined as tumor size <750 mm3) in all LuCaP35 tumors treated with castration alone (Cx) vs. castration + dutasteride (Cx + Dut) (A), and in tumors enrolled into treatment when tumors were <250 mm3 (B). P-values for curve comparisons were generated using the Mantel-Haenszel logrank test. Mean tumor volume growth curves at the indicated days post enrollment in LuCaP35 tumors enrolled into treatment when tumors were <250 mm3 (C), between 250–400 mm3 (D), and >400 mm3 (E). Dutasteride treatment was continued for 8 weeks (denoted by black line above x-axis) in the castration + dutasteride group.

Mentions: To further examine tumor characteristics associated with response to pre-receptor AR pathway inhibition, we determined whether response to treatment was related to tumor size at initiation of therapy. Although the study was designed to begin treatment at a tumor volume of ∼300 mm3, logistics of the animal experiments resulted in a measureable variation in tumor size at study entry. We arbitrarily grouped tumors into cohorts of <250 mm3, 250–400 mm3, and >400 mm3 at enrollment and compared the effect of castration vs. castration plus dutasteride within each group. Notably, the significant improvement in median survival imparted by dutasteride in the entire LuCaP35 cohort (from 152 to 337 days, HR for progression 2.8 [95% CI 1.4–4.6], p = 0.0015; Figure 3A), appeared predominately due to an impact on tumors that were smallest (<250 mm3) at the time of enrollment (HR for progression 7.3 [95%CI 2.2–30], p<0.0015, vs. castration alone; Figure 3B). In contrast, the combination of castration plus 8 weeks of dutasteride did not statistically impact PFS in tumors measuring 250–400 mm3 or >400 mm3 at enrollment (not shown); however, this may reflect decreased power associated with the post-hoc sub-classification of the groups.


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)

Response to dutasteride by tumor size at enrollment in LuCaP35 xenografts.Kaplan-Meier plots of progression free survival (defined as tumor size <750 mm3) in all LuCaP35 tumors treated with castration alone (Cx) vs. castration + dutasteride (Cx + Dut) (A), and in tumors enrolled into treatment when tumors were <250 mm3 (B). P-values for curve comparisons were generated using the Mantel-Haenszel logrank test. Mean tumor volume growth curves at the indicated days post enrollment in LuCaP35 tumors enrolled into treatment when tumors were <250 mm3 (C), between 250–400 mm3 (D), and >400 mm3 (E). Dutasteride treatment was continued for 8 weeks (denoted by black line above x-axis) in the castration + dutasteride group.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111545-g003: Response to dutasteride by tumor size at enrollment in LuCaP35 xenografts.Kaplan-Meier plots of progression free survival (defined as tumor size <750 mm3) in all LuCaP35 tumors treated with castration alone (Cx) vs. castration + dutasteride (Cx + Dut) (A), and in tumors enrolled into treatment when tumors were <250 mm3 (B). P-values for curve comparisons were generated using the Mantel-Haenszel logrank test. Mean tumor volume growth curves at the indicated days post enrollment in LuCaP35 tumors enrolled into treatment when tumors were <250 mm3 (C), between 250–400 mm3 (D), and >400 mm3 (E). Dutasteride treatment was continued for 8 weeks (denoted by black line above x-axis) in the castration + dutasteride group.
Mentions: To further examine tumor characteristics associated with response to pre-receptor AR pathway inhibition, we determined whether response to treatment was related to tumor size at initiation of therapy. Although the study was designed to begin treatment at a tumor volume of ∼300 mm3, logistics of the animal experiments resulted in a measureable variation in tumor size at study entry. We arbitrarily grouped tumors into cohorts of <250 mm3, 250–400 mm3, and >400 mm3 at enrollment and compared the effect of castration vs. castration plus dutasteride within each group. Notably, the significant improvement in median survival imparted by dutasteride in the entire LuCaP35 cohort (from 152 to 337 days, HR for progression 2.8 [95% CI 1.4–4.6], p = 0.0015; Figure 3A), appeared predominately due to an impact on tumors that were smallest (<250 mm3) at the time of enrollment (HR for progression 7.3 [95%CI 2.2–30], p<0.0015, vs. castration alone; Figure 3B). In contrast, the combination of castration plus 8 weeks of dutasteride did not statistically impact PFS in tumors measuring 250–400 mm3 or >400 mm3 at enrollment (not shown); however, this may reflect decreased power associated with the post-hoc sub-classification of the groups.

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