Article Figures & Data
Figures
- Figure 1.
Changes in serum PSA levels in LuCaP23CR and LuCaP35CR prostate cancer xenografts in response to treatment with abiraterone. Castrate male SCID mice were implanted subcutaneously with LuCaP23CR or LuCaP35CR tumors and randomly assigned to vehicle control or abiraterone treatment for 21 days. Serum PSA curves for control (blue) or Abi-T mice (red) are shown for individual mice bearing LuCaP23CR (A) and LuCaP35CR (B) xenografts. The segment of the y-axis denoted by the heavy bar in each graph is enlarged and presented in the adjacent panels on an expanded y-axis to more clearly show the decline in serum PSA over the first approximately 10 to 15 days after initiation of treatment.
- Figure 2.
Tumor growth and survival in LuCaP23CR and LuCaP35CR prostate cancer xenografts treated with abiraterone. Castrate male SCID mice were implanted subcutaneously with LuCaP23CR (A and B) or LuCaP35CR (C and D) tumors and randomly assigned to vehicle control or abiraterone treatment for 21 days. Median tumor volume trajectories with 95% confidence bands for control (blue) or Abi-T mice (red) bearing the LuCaP23CR (A) and LuCaP35CR (C) xenografts. Kaplan–Meier plots of PFS (defined as tumor size < 1,000 mm3) in control or Abi-T mice bearing the LuCaP23CR (B) and LuCaP35CR (D) xenografts. P values for curve comparisons generated using the Mantel–Haenszel log-rank test.
- Figure 3.
Tumor testosterone (top) and DHT levels (bottom) in control and Abi-T LuCaP23CR (A, C) and LuCaP35CR (B, D) xenografts. Androgen levels in Abi-T xenografts were evaluated by mass spectrometry in tumors resected at early (days 7–21) or late time points after therapy. Abi-R tumors recurred (defined as progression to > 1,000 mm3) and were resected during the 21-day period of abiraterone treatment. Abi-T tumors recurred and were resected after the completion of abiraterone treatment. This occurred between days 24 to 42 for LuCap23CR tumors, and between days 29 to 67 for LuCaP35CR (none of which recurred during the abiraterone-treatment period). P values represent unpaired 2-sided t tests between the indicated groups. The values of P < 0.05 were considered significant. One P value in panel D (in italics) is included as trending toward statistical significance (P < 0.10).
- Figure 4.
Expression of full-length and truncated AR splice variants in LuCaP23CR and LuCaP35CR tumors treated with abiraterone compared with vehicle control. Transcript levels for ARFL (A and B), the AR7 splice variant (C and D), and the ARdel567es splice variant (E and F) were measured by qRT-PCR in frozen LuCaP23CR (A, C, E) and LuCaP35CR (B, D, F) tumors. White circles denote vehicle treated controls. Black circles denote tumors resected while on abiraterone treatment, either at early time points (d7-21) or at Abi-R regrowth. Gray circles denote Abi-T tumors which recurred and were resected after completion of abiraterone treatment. Fold changes are calculated from the difference in mean ΔCt's between abiraterone treated and vehicle treated controls (ΔΔCt method; fold = 2ΔΔCt). P values from 2 sample t tests. The values of P < 0.05 were considered significant. The P values in panel D (in italics) are included as trending toward statistical significance (P < 0.10). n.s., not significant.
- Figure 5.
Expression of PSA and CYP17A1 in LuCaP23CR and LuCaP35CR tumors treated with abiraterone compared with vehicle control. Transcript levels for PSA (A and B) and CYP17A1 were measured by qRT-PCR in frozen LuCaP23CR (A, C) and LuCaP35CR (B, D) tumors. White circles denote vehicle treated controls. Black circles denote tumors resected while on abiraterone treatment, either at early time points (d7-21) or at Abi-R regrowth. Gray circles denote Abi-T tumors which recurred and were resected after completion of abiraterone treatment. Fold changes are calculated from the difference in mean ΔCt's between abiraterone-treated and vehicle-treated controls (ΔΔCt method; fold = 2ΔΔCt). P values from 2 sample t tests. The values of P < 0.05 were considered significant.
- Figure 6.
The pathways of androgen biosynthesis. In the classical pathway (solid gray arrow), C21 precursors (pregnenolone and progesterone) are converted to the C19 adrenal androgens DHEA and androstenedione (AED) by the sequential hydroxylase and lyase activity of CYP17A1. DHEA and AED are converted to testosterone by a series of reactions involving the activity of HSD3B1 and 2, HSD17B3 and AKR1C3 enzymes. Testosterone is converted to the potent androgen DHT by the activity of SRD5A1 and 2. Oxidative 3 α-HSD enzymes [including HSD17B6 (RL-HSD), HSD17B10, HSD17B13 (DHRS9), RODH4, and RDH5] can act to inhibit the prereceptor catabolism of DHT. An alternative pathway (short gray arrows) has also been proposed in which C21 precursors are first acted upon by SRD5A and the reductive activity of AKR1C2, followed by CYP17A1, HSD17B3, and subsequent oxidation to DHT. Adapted from ref. 42 with permission.
Tables
- Table 1.
Changes in AR and steroidogenic gene expression in Abi-T CRPC xenografts
LuCaP 23 CR LuCaP 35 CR Time point of resection Early (d7) Abirateronea resistant (d11-21) Abirateroneb treated (d24-42) Early (d7-21) Abirateroneb treated (d29-67) Gene and function Foldc Pd Fold P Fold P Fold P Fold P AR ARFL 2.7 P < 0.0001 2.3 0.008 2.5 0.028 3.4 0.001 ARdel567es 2.2 0.026 2.7 0.036 7.6 0.078 5.2 0.073 ARV7 3.1 0.0003 AR-regulated genes PSA −3.4 0.003 −2.0 0.023 NKX3.1 −1.2 0.026 −1.9 0.038 −1.6 0.036 FKBP5 −1.6 0.004 −3.0 P < 0.0001 −2.7 P < 0.0001 −3.8 0.002 TMPRSS2 −1.3 0.005 −1.6 P < 0.0001 Cholesterol import and processing SCARB1 −1.5 0.042 LDLR −3.0 0.001 −1.9 0.003 LIPE 4.5 P < 0.0001 7.1 P < 0.0001 SCAP 1.8 0.003 2.6 P < 0.0001 1.3 0.024 CYP11A1 1.3 0.022 1.2 0.031 1.6 0.0003 STAR 1.5 0.002 1.5 0.018 STARD3 1.8 0.003 2.4 P < 0.0001 STARD4 −1.6 P < 0.0001 −1.4 0.007 −2.6 0.004 1.6 0.057 STARD5 1.5 0.005 1.7 0.006 1.8 0.003 CYP17A1 and cofactors CYP17A1 1.6 0.022 1.7 0.0002 2.1 0.0001 2.2 0.028 HNF1A 1.7 0.004 1.8 0.003 2.1 0.003 HNF4A −1.7 0.01 22.7 0.015 NR5A1 (SF-1) 1.3 0.02 1.3 0.04 1.5 0.010 CYB5A 1.4 0.0001 POR 1.6 P < 0.0001 2.1 P < 0.0001 −1.5 0.0002 1.2 0.043 DAX1 2.8 0.03 2.0 0.043 DUSP 1.7 0.026 −3.1 P < 0.0001 Conversion of C-19 steroids to T and DHT HSD3B1 HSD3B2 1.5 0.050 1.7 0.063 HSD17B3 1.3 0.006 1.4 0.003 2.2 0.001 AKR1C3 1.6 0.086 1.9 0.001 1.6 0.053 5.2 P < 0.0001 SDR5A1 −1.4 0.004 SDR5A2 1.9 0.028 3.5 P < 0.0001 4.5 P < 0.0001 SDR5A3 1.2 0.038 1.4 P < 0.0001 1.7 P < 0.0001 CYP19A 1.7 0.009 2.5 0.001 2.5 0.037 Prereceptor regulation of DHT AKR1C2 4.2 P < 0.0001 3.9 0.001 3.3 0.0001 HSD17B10 RODH 4 −2.9 0.000 −4.8 P < 0.0001 −5.9 P < 0.0001 −1.8 0.024 RDH5 2.8 0.0001 RLHSD (HSD17B6) −4.3 0.003 −26.6 P < 0.0001 −26.2 P < 0.0001 −27.3 P < 0.0001 −4.8 0.001 DHRS9 (HSD17B13) 3.7 0.0001 7.5 P < 0.0001 −6.3 0.0003 Glucuronide formation UGDH 1.7 0.006 2.3 P < 0.0001 −1.6 0.016 UGT2B15 4.6 P < 0.0001 9.3 P < 0.0001 5.1 0.002 UGT2B17 2.6 0.0001 3.6 P < 0.0001 UGT2B17 is deleted in LuCaP35CR -
aAbiraterone resistant tumors recurred (size 1,000 mm3) and were resected while on abiraterone.
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bAbiraterone treated tumors recurred (size 1,000 mm3) after the 21 day treatment period.
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cFold change from difference in mean ΔCt's (ΔΔCt method; fold = 2ΔΔCt) between controls and Abi-T tumors in the indicated groups (early, resistant, or treated). Fold changes for genes which were not statistically significant are omitted.
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dP values from 2 sample t tests. The values of P ≤ 0.05 were considered significant. Genes with the values of P < 0.10 were considered trending toward significance if fold change was also 1.5 or more (shown in italics).
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Supplementary Data
Files in this Data Supplement:
- Supplementary Table 1 - PDF file - 20K
Volume 17, Issue 18
