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- W4361961519 abstract "<div>Abstract<p><b>Purpose:</b> Abiraterone is a potent inhibitor of the steroidogenic enzyme CYP17A1 and suppresses tumor growth in patients with castration-resistant prostate cancer (CRPC). The effectiveness of abiraterone in reducing tumor androgens is not known, nor have mechanisms contributing to abiraterone resistance been established.</p><p><b>Experimental Design:</b> We treated human CRPC xenografts with abiraterone and measured tumor growth, tissue androgens, androgen receptor (AR) levels, and steroidogenic gene expression versus controls.</p><p><b>Results:</b> Abiraterone suppressed serum PSA levels and improved survival in two distinct CRPC xenografts: median survival of LuCaP35CR improved from 17 to 39 days (HR = 3.6, <i>P</i> = 0.0014) and LuCaP23CR from 14 to 24 days (HR = 2.5, <i>P</i> = 0.0048). Abiraterone strongly suppressed tumor androgens, with testosterone (T) decreasing from 0.49 ± 0.22 to 0.03 ± 0.01 pg/mg (<i>P</i> < 0.0001), and from 0.69 ± 0.36 to 0.03 ± 0.01 pg/mg (<i>P</i> = 0.002) in abiraterone-treated 23CR and 35CR, respectively, with comparable decreases in tissue DHT. Treatment was associated with increased expression of full-length AR (AR<sup>FL</sup>) and truncated AR variants (AR<sup>FL</sup> 2.3-fold, <i>P</i> = 0.008 and AR<sup>del567es</sup> 2.7-fold, <i>P</i> = 0.036 in 23 CR; AR<sup>FL</sup> 3.4-fold, <i>P</i> = 0.001 and AR<sup>V7</sup> 3.1-fold, <i>P</i> = 0.0003 in 35CR), and increased expression of the abiraterone target CYP17A1 (∼2.1-fold, <i>P</i> = 0.0001 and <i>P</i> = 0.028 in 23CR and 35CR, respectively) and transcript changes in other enzymes modulating steroid metabolism.</p><p><b>Conclusions:</b> These studies indicate that abiraterone reduces CRPC growth via suppression of intratumoral androgens and that resistance to abiraterone may occur through mechanisms that include upregulation of CYP17A1, and/or induction of AR and AR splice variants that confer ligand-independent AR transactivation. <i>Clin Cancer Res; 17(18); 5913–25. ©2011 AACR</i>.</p></div>" @default.
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- W4361961519 date "2023-03-31" @default.
- W4361961519 modified "2023-10-18" @default.
- W4361961519 title "Data from Resistance to CYP17A1 Inhibition with Abiraterone in Castration-Resistant Prostate Cancer: Induction of Steroidogenesis and Androgen Receptor Splice Variants" @default.
- W4361961519 doi "https://doi.org/10.1158/1078-0432.c.6519947" @default.
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