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

Authors
SG Liva, YC Tseng, AM Dauki, MG Sovic, T Vu et al

Lab
Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA

Journal
EMBO Molecular Medicine

Abstract
No approved therapy exists for cancer-associated cachexia. Thecolon-26mouse 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-42exhibited 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-42provided limited anti-cachectic benefits, but, in combination with GTx-024, significantly improved bodyweight, hindlimb muscle mass, and grip strength versus controls.AR-42suppressed the IL-6/GP130/STAT3signaling axis in muscle without impacting circulating cytokines. GTx-024-mediatedb-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-024therapy and a blockade of GTx-024-mediatedanabolic signaling. AR-42mitigates 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.

BIOSEB Instruments Used:
Grip strength test (BIO-GS3)