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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 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, hind limb 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE138464 | GEO | 2019/11/20

REPOSITORIES: GEO

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Preclinical investigation of the novel histone deacetylase inhibitor AR-42 in the treatment of cancer-induced cachexia

Project description:Purpose: We assessed the anti-cachectic activity of the novel HDAC inhibitor AR-42 in murine models of cancer cachexia. Methods: Effects on classic features of cachexia, including decreased body weight, skeletal muscle and adipose tissue mass, muscle fiber cross-sectional area, and muscle strength, and increased intramuscular mRNA expression of E3 ligases Atrogin-1/MAFbx and MuRF1 were examined. Metabolomic analysis, whole transcriptome shotgun sequencing (RNA-seq) analysis, and cytokine profiling were used to compare metabolic phenotype and mRNA expression profiles in muscle, and cytokine production in serum, respectively, in AR-42- and vehicle-treated tumor-bearing and tumor-free control mice. Results: Orally administered AR-42 suppressed cancer cachexia in the C-26 colon adenocarcinoma model. This anti-cachectic effect, also confirmed in Lewis lung carcinoma-bearing mice, was not observed after treatment with other HDAC inhibitors (vorinostat, romidepsin). Cytokine profiling and RNA-seq analyses revealed effects of AR-42 on tumor-induced changes in inflammatory cytokine production and multiple transcriptional programs in muscle, including the inhibition of multiple pro-cachexia drivers, such as IL-6 and its receptor IL-6ra, leukemia inhibitory factor, Foxo1, Atrogin-1, MuRF1, adipose triglyceride lipase, uncoupling protein 3, and myocyte enhancer factor 2c. Metabolomic analysis indicated the reprogramming of skeletal muscle metabolism, including reduced glycolysis and glycogen synthesis and increased protein degradation, which was restored by AR-42 to a state characteristic of tumor-free mice. Conclusions: These findings support further investigation of AR-42 as part of a comprehensive therapeutic strategy for cancer cachexia.

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Overcoming Resistance to Anabolic SARM therapy in Experimental Cancer Cachexia with an HDAC Inhibitor

Project description:Overcoming Resistance to Anabolic SARM therapy in Experimental Cancer Cachexia with an HDAC Inhibitor

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