Abstract
18 Background: Abiraterone is a novel inhibitor of the steroidogenic enzyme CYP17 and suppresses tumor growth in patients with castration-resistant prostate cancer (CRPC). The efficacy of abiraterone in suppressing tumor androgens or mechanisms of resistance to abiraterone are not known. Methods: Human CRPC xenografts LuCaP 23 and LuCaP 35 grown in castrated male mice were treated with abiraterone to determine effects on tumor growth and tumor androgen levels. Tumor gene expression measurements were obtained to delineate mechanisms of abiraterone resistance. Results: Abiraterone i.p. for 21 days improved survival (time to tumor size 750 mm3) vs vehicle control (VC) in LuCaP 35 (HR 3.8 [95% CI 3.1-53.7] median survival 39 vs 18 days) and LuCap 23 (HR 2.4 [1.43-10.24] median survival 24 vs. 14 days). Greater anti-tumor activity correlated with superior tumor androgen suppression. Tumor testosterone was strongly suppressed in both LuCaP35 (0.20 + 0.24 vs VC 0.69 + 0.36 pg/mg) and LuCaP 23 (0.07 + 0.11 vs VC 0.49 + 0.22 pg/mg). DHT levels were also markedly suppressed in LuCaP35 (1.17 + 1.46 vs VC 3.49 + 1.81pg/mg). In contrast, DHT levels in LuCap23 were unchanged early (day 7-21) and only partially suppressed at longer time points (VC 5.73 + 1.88; early 5.31 + 2.69; late 2.82 + 2.27 pg/mg). Expression of the abiraterone target CYP17 was upregulated in both xenografts (LuCaP23 2.5 fold, p<0.0001; LuCap35 2.9 fold, p=0.028). Overall, LuCap23 appeared resistant to suppression of tumor androgens due to induction of steroidogenic transcripts (including STAR, CYP11, HSD3B1 and AKR1C3) without statistically significant increases in androgen receptor (AR). In contrast, LuCap35 demonstrated strong induction of transcripts for AR and AR splice variants (AR 3.8 fold, p<0.0001, V7 AR splice variant 3.7 fold, p<0.0001), with induction of steroidogenic transcripts only at late time points. Conclusions: Abiraterone treatment suppressed intratumoral androgen levels and reduced growth of CRPC xenografts. Abiraterone resistance may occur through upregulation of the abiraterone target CYP17, and/or the induction of AR and AR splice variants that confer ligand-independent AR trans-activation. [Table: see text]
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