TY - JOUR
T1 - Selective Glucocorticoid Receptor Modulators (SGRMs) delay castrate-resistant prostate cancer growth
AU - Kach, Jacob
AU - Long, Tiha M.
AU - Selman, Phillip
AU - Tonsing-Carter, Eva Y.
AU - Bacalao, Maria A.
AU - Lastra, Ricardo R.
AU - De Wet, Larischa
AU - Comiskey, Shane
AU - Gillard, Marc
AU - VanOpstall, Calvin
AU - West, Diana C.
AU - Chan, Wen Ching
AU - Vander Griend, Donald
AU - Conzen, Suzanne D.
AU - Szmulewitz, Russell Z.
N1 - Funding Information:
The authors would like to thank Friends Against Cancer for their philanthropic support. We would like to thank David Hosfield and Geoffrey Greene for generous supply of the Nu-GFP–labeled cell lines. The RNA sequencing was performed by the Functional Genomics Core Facility at the University of Chicago supported in part by the University of Chicago Medicine Comprehensive Cancer Center Cancer Center support grant (P30CA014599) under the direction of Pieter Faber. Dr. Andrade also contributed to the RNA-sequencing bioinformatics pipeline utilized for this study. This work was supported by Movember-Prostate Cancer Foundation Challenge Award, Cancer Research Foundation, and NIH SPORE 1P50CA180995. The Center for Research Informatics, under the direction of Jorge Andrade, was funded by the Biological Sciences Division at the University of Chicago with additional funding provided by the Institute for Translational Medicine, CTSA grant number UL1 TR000430 from the NIH. C. VanOpstall and L. de Wet were supported by Cancer Biology training grant T32 CA 009594. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
PY - 2017/8
Y1 - 2017/8
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-16-0923
DO - 10.1158/1535-7163.MCT-16-0923
M3 - Article
C2 - 28428441
AN - SCOPUS:85027112449
SN - 1535-7163
VL - 16
SP - 1680
EP - 1692
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 8
ER -