前列腺癌
糖皮质激素受体
雄激素受体
体内
癌症研究
米非司酮
药理学
恩扎鲁胺
雄激素
封锁
生长抑制
糖皮质激素
医学
癌症
细胞生长
受体
生物
内科学
激素
生物化学
怀孕
遗传学
生物技术
作者
Jacob Kach,Tiha M. Long,Phillip Selman,Eva Tonsing-Carter,Maria A. Bacalao,Ricardo R. Lastra,Larischa de Wet,Shane Comiskey,Marc Gillard,Calvin VanOpstall,Diana C. West,Wen-Ching Chan,Donald Vander Griend,Suzanne D. Conzen,Russell Z. Szmulewitz
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2017-08-01
卷期号:16 (8): 1680-1692
被引量:44
标识
DOI:10.1158/1535-7163.mct-16-0923
摘要
Abstract Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here, we report that two novel nonsteroidal and highly selective GR modulators (SGRM), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect androgen receptor (AR) signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR–expressing, but not in low GR–expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo. Together, these data suggest that GR-selective nonsteroidal SGRMs potently inhibit GR activity and prostate cancer growth despite AR pathway inhibition, demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC. Mol Cancer Ther; 16(8); 1680–92. ©2017 AACR.
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