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

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 non-steroidal and highly selective GR modulators (SGRMs), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer (PC) and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect 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 non-steroidal SGRMs potently inhibit GR activity and PC growth despite AR pathway inhibition demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC.

Glucocorticoid receptor upregulation increases radioresistance and triggers androgen independence of prostate cancer

“…In this study, we showed that GR promoted androgen‐independent survival of androgen‐dependent PCa cells. The role of GR in castration‐resistant survival was previously suggested by Kach et al While previous reports were based on the differences in GR levels in androgen‐dependent vs. castration‐resistant PCa cell line, our in vitro and in vivo data clearly showed direct evidence of GR contribution in converting androgen‐dependent LNCaP cells to the androgen‐independent (castration‐resistant) state. As C4‐2 is a castration‐resistant cell line, we could not observe any significant effect of GR signaling on further promoting androgen‐independent survival of these cells.…”

“…We then tested the transcription of GR downstream genes AKAP12 , CEBPD , FKBP5 , SGK1 , and ZBTB16 in radioresistant cells. As shown in Figure E, transcription of these genes was activated in radioresistant cells compared with parental cells.…”

“…In addition, as mifepristone has been known to also inhibit the progesterone receptor (PR) signaling pathway in addition to the GR signaling pathway, development of highly GR‐selective nonsteroidal drugs seems essential. Recently, novel nonsteroidal and highly selective GR modulators (SGRM) CORT118335 and CORT108297 have demonstrated the ability to block GR activity in PCa and slow CRPC progression …”

Octahydrocyclopenta[c]pyridine Scaffold – Enantioselective Synthesis and Indole Annulation

“…Therefore, CORT 108297 ( 4 ) seems to be a promising replacement for mifepristone ( 3 ) in the near future. Furthermore, promising activity of this compound against prostate cancer was recently reported …”

Beyond the androgen receptor II: New approaches to understanding and treating metastatic prostate cancer; Report from the 2017 Coffey‐Holden Prostate Cancer Academy Meeting

“…GR expression also has a role in driving tumor survival and poor outcomes in breast cancer models . These findings offer an opportunity for GR targeting in CRPC with epigenetic modulators that affect GR transcription or with direct GR inhibition . There are likely to be additional epigenetic mechanisms of GR activation amenable to alterative targeting approaches, including dysregulation of glucocorticoid metabolism in tumors through enzalutamide‐mediated loss of expression of the metabolic enzyme 11β‐HSD2 …”