Selective Glucocorticoid Receptor Modulators (SGRMs) delay castrate-resistant prostate cancer growth

Jacob Kach, Tiha M. Long, Phillip Selman, Eva Y. 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

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1680-1692
Number of pages13
JournalMolecular Cancer Therapeutics
Volume16
Issue number8
DOIs
StatePublished - Aug 2017
Externally publishedYes

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Glucocorticoid Receptors
Prostatic Neoplasms
Growth
Castration
Androgen Receptors
Mifepristone

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kach, J., Long, T. M., Selman, P., Tonsing-Carter, E. Y., Bacalao, M. A., Lastra, R. R., ... Szmulewitz, R. Z. (2017). Selective Glucocorticoid Receptor Modulators (SGRMs) delay castrate-resistant prostate cancer growth. Molecular Cancer Therapeutics, 16(8), 1680-1692. https://doi.org/10.1158/1535-7163.MCT-16-0923

Selective Glucocorticoid Receptor Modulators (SGRMs) delay castrate-resistant prostate cancer growth. / Kach, Jacob; Long, Tiha M.; Selman, Phillip; Tonsing-Carter, Eva Y.; Bacalao, Maria A.; Lastra, Ricardo R.; De Wet, Larischa; Comiskey, Shane; Gillard, Marc; VanOpstall, Calvin; West, Diana C.; Chan, Wen Ching; Vander Griend, Donald; Conzen, Suzanne D.; Szmulewitz, Russell Z.

In: Molecular Cancer Therapeutics, Vol. 16, No. 8, 08.2017, p. 1680-1692.

Research output: Contribution to journalArticle

Kach, J, Long, TM, Selman, P, Tonsing-Carter, EY, Bacalao, MA, Lastra, RR, De Wet, L, Comiskey, S, Gillard, M, VanOpstall, C, West, DC, Chan, WC, Vander Griend, D, Conzen, SD & Szmulewitz, RZ 2017, 'Selective Glucocorticoid Receptor Modulators (SGRMs) delay castrate-resistant prostate cancer growth', Molecular Cancer Therapeutics, vol. 16, no. 8, pp. 1680-1692. https://doi.org/10.1158/1535-7163.MCT-16-0923
Kach, Jacob ; Long, Tiha M. ; Selman, Phillip ; Tonsing-Carter, Eva Y. ; Bacalao, Maria A. ; Lastra, Ricardo R. ; De Wet, Larischa ; Comiskey, Shane ; Gillard, Marc ; VanOpstall, Calvin ; West, Diana C. ; Chan, Wen Ching ; Vander Griend, Donald ; Conzen, Suzanne D. ; Szmulewitz, Russell Z. / Selective Glucocorticoid Receptor Modulators (SGRMs) delay castrate-resistant prostate cancer growth. In: Molecular Cancer Therapeutics. 2017 ; Vol. 16, No. 8. pp. 1680-1692.
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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.",
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AU - VanOpstall, Calvin

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