Cargando…

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)...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005646/
https://www.ncbi.nlm.nih.gov/pubmed/31930715
http://dx.doi.org/10.15252/emmm.201809910
_version_ 1783494981334335488
author 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
author_facet 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
author_sort Liva, Sophia G
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7005646
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-70056462020-02-13 Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor 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 EMBO Mol Med Articles 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. John Wiley and Sons Inc. 2020-01-13 2020-02-07 /pmc/articles/PMC7005646/ /pubmed/31930715 http://dx.doi.org/10.15252/emmm.201809910 Text en © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
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
Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor
title Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor
title_full Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor
title_fullStr Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor
title_full_unstemmed Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor
title_short Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor
title_sort overcoming resistance to anabolic sarm therapy in experimental cancer cachexia with an hdac inhibitor
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7005646/
https://www.ncbi.nlm.nih.gov/pubmed/31930715
http://dx.doi.org/10.15252/emmm.201809910
work_keys_str_mv AT livasophiag overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT tsengyuchou overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT daukianeesm overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT sovicmichaelg overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT vutrang overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT hendersonsallye overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT kuoyichiu overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT benedictjasona overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT zhangxiaoli overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT remailybryanc overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT kulpsamuelk overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT campbellmoray overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT bekaiisaabtanios overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT phelpsmitchella overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT chenchingshih overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor
AT cosschristopherc overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor