ABSTRACT
Purpose The common colon-26 mouse (C-26) model of experimental cachexia mimics recent late stage clinical failures of anabolic anti-cachexia therapy, and does not respond to the anabolic selective androgen receptor modulator (SARM) GTx-024. Based on the demonstrated anti-cachectic efficacy of the histone deacetylase inhibitor (HDACi) AR-42 in this model, we hypothesized that combined SARM/AR-42 would provide improved anti-cachectic efficacy.
Design In the C-26 model, we determined a reduced efficacious dose of AR-42 which was combined with anabolic SARM therapy and evaluated for anti-cachectic efficacy. The effects of treatment and tumor burden on anabolic and catabolic signaling occurring in skeletal muscle were characterized using muscle performance parameters and RNA-seq.
Results Anabolic anti-cachexia therapy with diverse androgens had no impact on cachectic outcomes in the C-26 model. A reduced dose of the HDACi AR-42 alone provided limited anti-cachectic benefits, but when combined with the SARM GTx-024, significantly improved bodyweight (p<0.0001), hind limb muscle mass (p<0.05), and voluntary grip strength (p<0.0001) versus tumor-bearing controls. Reduced-dose AR-42 treatment suppressed the IL-6/GP130/STAT3 signaling axis without significantly impacting circulating cytokine levels. GTx-024-mediated β-catenin target gene regulation was apparent in cachectic mice only when combined with AR-42.
Conclusions Cachectic signaling in the C-26 model is comprised of catabolic signaling insensitive to anabolic GTx-024 therapy and a blockade of GTx-024-mediated anabolic signaling. AR-42 treatment mitigates catabolic gene activation and restores anabolic responsiveness to GTx-024. Combining GTx-024, a clinically established anabolic therapy, with a low dose of AR-42, a clinically evaluated HDACi, represents a promising approach to improve anabolic response in cachectic patient populations.
Footnotes
Financial support: This work was supported in part by NCI/NIH K12-CA133250-07 (C. Coss), Eli Lilly Fellowship (S. Liva) and Pelotonia Idea Award (OSU Comprehensive Cancer Center, C. Coss).
Conflict of interest: C.-S. Chen is an inventor of AR-42, which was licensed to Arno Therapeutics, Inc., for clinical development by The Ohio State University Research Foundation. C.C. Coss is a former employee of GTx, Inc., owner of GTx-024, but has no financial relationship with or any equity in GTx, Inc. Arno Therapeutics, Inc. and GTx, Inc. were not involved in any way with the financing, design, or interpretation of the reported studies. All other authors have no conflicts of interest to declare.
TRANSLATIONAL RELEVANCE: Our data provide insight into the recent late stage clinical failure of SARM anti-cachectic therapy by characterizing anabolic resistance in the C-26 model of cancer cachexia. We show that fully anabolic doses of multiple androgens provide no anti-cachectic efficacy and that SARM-mediated WNT activation in skeletal muscle is disrupted by cachectic signaling. To the best of our knowledge, this is the first study to characterize WNT-mediated anabolic resistance in experimental cachexia. We further show that the novel HDACi AR-42 suppresses the IL-6/GP130/STAT3 axis within skeletal muscle to provide anti-cachectic benefit that is additionally associated with improved anabolic response to co-administered SARM. Our data support combined SARM/AR-42 administration as improved anti-cachectic therapy.