Overcoming Resistance to Anabolic Selective Androgen Receptor Modulator (SARM) Therapy in Experimental Cancer Cachexia with Histone Deacetylase Inhibitor AR-42

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.