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

EMBO Mol Med. 2020 Feb 7;12(2):e9910. doi: 10.15252/emmm.201809910. Epub 2020 Jan 13.

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.

Keywords: HDAC inhibitor; STAT3; androgen; cachexia; selective androgen receptor modulator.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androgens / therapeutic use*
  • Animals
  • Cachexia / drug therapy*
  • Drug Resistance, Neoplasm*
  • Female
  • Histone Deacetylase Inhibitors / therapeutic use*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neoplasms*

Substances

  • Androgens
  • Histone Deacetylase Inhibitors

Associated data

  • GEO/GSE138464