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

Sophia G Liva, Yu-Chou Tseng, Anees M Dauki, Michael G Sovic, Trang Vu, Sally E Henderson, Yi-Chiu Kuo, Jason A Benedict, Xiaoli Zhang, Bryan C Remaily, Samuel K Kulp, Moray Campbell, Tanios Bekaii-Saab, Mitchell A Phelps, Ching-Shih Chen, Christopher C Coss
EMBO Molecular Medicine 2020 February 7, 12 (2): e9910
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.

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