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

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

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 modulato...

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Main Authors: 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
Format: Article
Language:English
Published: Springer Nature 2020-01-01
Series:EMBO Molecular Medicine
Subjects:
androgen
cachexia
HDAC inhibitor
selective androgen receptor modulator
STAT3
Online Access:https://doi.org/10.15252/emmm.201809910
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Summary: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.
ISSN:1757-4676
1757-4684

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