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

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 ) GT x‐024. The histone deacetylase inhibitor ( HDAC i) 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 GT x‐024, significantly improved body weight, hindlimb muscle mass, and grip strength versus controls. AR ‐42 suppressed the IL ‐6/ GP 130/ STAT 3 signaling axis in muscle without impacting circulating cytokines. GT x‐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 GT x‐024 therapy and a blockade of GT x‐024‐mediated anabolic signaling. AR ‐42 mitigates catabolic gene activation and restores anabolic responsiveness to GT x‐024. Combining GT x‐024, a clinically established anabolic therapy, with AR ‐42, a clinically evaluated HDAC i, represents a promising approach to improve anabolic response in cachectic patients.