Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor. Issue 2 (13th January 2020)

• Record Type: Journal Article
• Authors: Liva, Sophia G; Tseng, Yu‐Chou; Dauki, Anees M; Sovic, Michael G; Vu, Trang; Henderson, Sally E; Kuo, Yi‐Chiu; Benedict, Jason A; Zhang, Xiaoli; Remaily, Bryan C; Kulp, Samuel K; Campbell, Moray; Bekaii‐Saab, Tanios; Phelps, Mitchell A; Chen, Ching‐Shih; Coss, Christopher C
• Is Part Of: EMBO molecular medicine. Volume 12:Issue 2(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-01-13
• Subjects: androgen -- cachexia -- HDAC inhibitor -- selective androgen receptor modulator -- STAT3; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201809910
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: 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. Synopsis: Cancer cachexia increases morbidity and mortality of cancer patients. Given the multifactorial pathogenesis of cachexia, effective treatment remains elusive. Here, a novel therapeutic strategy combining anti‐catabolic and anabolic activities is established in a murine model of cancer cachexia. Anabolic androgen monotherapy with the SARM GTx‐024 was ineffective in preventing skeletal muscle and body weight loss. Transcriptomic analyses revealed that the HDAC inhibitor AR‐42 exerted anti‐cachectic activity via modulation of the IL‐6 axis in skeletal muscle. The anabolic efficacy of GTx‐024 was dependent on functional WNT/β‐catenin signaling in skeletal muscle. Cachectic burden disrupted skeletal muscle WNT/β‐catenin signaling, but the anti‐cachectic activity could be restored by co‐administration of the HDAC inhibitor AR‐42. Abstract : Cancer cachexia increases morbidity and mortality of cancer patients. Given the multifactorial pathogenesis of cachexia, effective treatment remains elusive. Here, a novel therapeutic strategy combining anti‐catabolic and anabolic activities is established in a murine model of cancer cachexia.