Format

Send to

Choose Destination
Mol Cancer Ther. 2017 Aug;16(8):1680-1692. doi: 10.1158/1535-7163.MCT-16-0923. Epub 2017 Apr 20.

Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth.

Author information

1
Department of Medicine, The University of Chicago, Chicago, Illinois.
2
Department of Anatomical Pathology, The University of Chicago, Chicago, Illinois.
3
Department of Surgery, The University of Chicago, Chicago, Illinois.
4
Center for Research Informatics, The University of Chicago, Chicago, Illinois.
5
Ben May Department for Cancer Research, The University of Chicago, Chicago, Illinois.
6
Department of Medicine, The University of Chicago, Chicago, Illinois. rszmulew@medicine.bsd.uchicago.edu.

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.

PMID:
28428441
PMCID:
PMC5544558
DOI:
10.1158/1535-7163.MCT-16-0923
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center