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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2020-01-01
|
| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201809910 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849342561221607424 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Sophia G Liva |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e590447d2f534e9b86dfa986d39f3eb8 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-e590447d2f534e9b86dfa986d39f3eb82025-08-20T03:43:21ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-01-0112212110.15252/emmm.201809910Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitorSophia G Liva0Yu‐Chou Tseng1Anees M Dauki2Michael G Sovic3Trang Vu4Sally E Henderson5Yi‐Chiu Kuo6Jason A Benedict7Xiaoli Zhang8Bryan C Remaily9Samuel K Kulp10Moray Campbell11Tanios Bekaii‐Saab12Mitchell A Phelps13Ching‐Shih Chen14Christopher C Coss15Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State UniversityDivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State UniversityDivision of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State UniversityDivision of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State UniversityDivision of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State UniversityDepartment of Veterinary Biosciences, College of Veterinary Medicine, Ohio State UniversityDivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State UniversityCenter for Biostatistics, Department of Biomedical Informatics, The Ohio State UniversityCenter for Biostatistics, Department of Biomedical Informatics, The Ohio State UniversityDivision of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State UniversityDivision of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State UniversityDivision of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State UniversityMayo Clinic Cancer CenterDivision of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State UniversityDivision of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State UniversityDivision of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State UniversityAbstract 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.https://doi.org/10.15252/emmm.201809910androgencachexiaHDAC inhibitorselective androgen receptor modulatorSTAT3 |
| spellingShingle | 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 Overcoming resistance to anabolic SARM therapy in experimental cancer cachexia with an HDAC inhibitor EMBO Molecular Medicine androgen cachexia HDAC inhibitor selective androgen receptor modulator STAT3 |
| 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 | androgen cachexia HDAC inhibitor selective androgen receptor modulator STAT3 |
| url | https://doi.org/10.15252/emmm.201809910 |
| work_keys_str_mv | AT sophiagliva overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT yuchoutseng overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT aneesmdauki overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT michaelgsovic overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT trangvu overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT sallyehenderson overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT yichiukuo overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT jasonabenedict overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT xiaolizhang overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT bryancremaily overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT samuelkkulp overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT moraycampbell overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT taniosbekaiisaab overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT mitchellaphelps overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT chingshihchen overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor AT christopherccoss overcomingresistancetoanabolicsarmtherapyinexperimentalcancercachexiawithanhdacinhibitor |