Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor

Sophia G. Liva, Yu Chou Tseng, Anees M. Dauki, Michael G. Sovic, Trang Vu, Sally E. Henderson, Yi Chiu Kuo, Jason A. Benedict, Xiaoli Zhang, Bryan C. Remaily, Samuel K. Kulp, Moray Campbell, Tanios Bekaii-Saab, Mitchell A. Phelps, Ching Shih Chen, Christopher C. Coss

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

No approved therapy exists for cancer-associated cachexia. The colon-26 mouse model of cancer cachexia mimics recent late-stage clinical failures of anabolic anti-cachexia therapy and was unresponsive to anabolic doses of diverse androgens, including the selective androgen receptor modulator (SARM) GTx-024. The histone deacetylase inhibitor (HDACi) AR-42 exhibited anti-cachectic activity in this model. We explored combined SARM/AR-42 therapy as an improved anti-cachectic treatment paradigm. A reduced dose of AR-42 provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR-42 suppressed the IL-6/GP130/STAT3 signaling axis in muscle without impacting circulating cytokines. GTx-024-mediated β-catenin target gene regulation was apparent in cachectic mice only when combined with AR-42. Our data suggest cachectic signaling in this model involves catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patients.

Original languageEnglish (US)
Article numbere9910
JournalEMBO Molecular Medicine
Volume12
Issue number2
DOIs
StatePublished - Feb 7 2020

Keywords

  • HDAC inhibitor
  • STAT3
  • androgen
  • cachexia
  • selective androgen receptor modulator

ASJC Scopus subject areas

  • Molecular Medicine

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    Liva, S. G., Tseng, Y. C., Dauki, A. M., Sovic, M. G., Vu, T., Henderson, S. E., Kuo, Y. C., Benedict, J. A., Zhang, X., Remaily, B. C., Kulp, S. K., Campbell, M., Bekaii-Saab, T., Phelps, M. A., Chen, C. S., & Coss, C. C. (2020). Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor. EMBO Molecular Medicine, 12(2), [e9910]. https://doi.org/10.15252/emmm.201809910