PMID- 27462398 OWN - NLM STAT- MEDLINE DCOM- 20171023 LR - 20211204 IS - 2044-5040 (Electronic) IS - 2044-5040 (Linking) VI - 6 DP - 2016 TI - ActRII blockade protects mice from cancer cachexia and prolongs survival in the presence of anti-cancer treatments. PG - 26 LID - 10.1186/s13395-016-0098-2 [doi] LID - 26 AB - BACKGROUND: Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life, and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti-cancer agents has not been elucidated yet. METHODS: In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model. CDD866 (murinized version of bimagrumab) is a neutralizing antibody against the activin receptor type II (ActRII) preventing binding of ligands such as myostatin and activin A, which are involved in cancer cachexia. CDD866 was evaluated in association with cisplatin as a standard cytotoxic agent or with everolimus, a molecular-targeted agent against mammalian target of rapamycin (mTOR). In the early studies, the treatment effect on cachexia was investigated, and in the additional studies, the treatment effect on progression of cancer and the associated cachexia was evaluated using body weight loss or tumor volume as interruption criteria. RESULTS: Cisplatin accelerated body weight loss and tended to exacerbate skeletal muscle loss in cachectic animals, likely due to some toxicity of this anti-cancer agent. Administration of CDD866 alone or in combination with cisplatin protected from skeletal muscle weight loss compared to animals receiving only cisplatin, corroborating that ActRII inhibition remains fully efficacious under cisplatin treatment. In contrast, everolimus treatment alone significantly protected the tumor-bearing mice against skeletal muscle weight loss caused by CT-26 tumor. CDD866 not only remains efficacious in the presence of everolimus but also showed a non-significant trend for an additive effect on reversing skeletal muscle weight loss. Importantly, both combination therapies slowed down time-to-progression. CONCLUSIONS: Anti-ActRII blockade is an effective intervention against cancer cachexia providing benefit even in the presence of anti-cancer therapies. Co-treatment comprising chemotherapies and ActRII inhibitors might constitute a promising new approach to alleviate chemotherapy- and cancer-related wasting conditions and extend survival rates in cachectic cancer patients. FAU - Hatakeyama, Shinji AU - Hatakeyama S AUID- ORCID: 0000-0002-0166-2773 AD - MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. FAU - Summermatter, Serge AU - Summermatter S AD - MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. FAU - Jourdain, Marie AU - Jourdain M AD - MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. FAU - Melly, Stefan AU - Melly S AD - MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. FAU - Minetti, Giulia C AU - Minetti GC AD - MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. FAU - Lach-Trifilieff, Estelle AU - Lach-Trifilieff E AD - MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland. LA - eng PT - Journal Article DEP - 20160726 PL - England TA - Skelet Muscle JT - Skeletal muscle JID - 101561193 RN - 0 (Antibodies, Blocking) RN - 0 (Antibodies, Monoclonal) RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Antineoplastic Agents) RN - 9HW64Q8G6G (Everolimus) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.30 (Activin Receptors, Type II) RN - EC 2.7.11.30 (activin receptor type II-A) RN - N15SW1DIV8 (bimagrumab) RN - Q20Q21Q62J (Cisplatin) SB - IM MH - Activin Receptors, Type II/*antagonists & inhibitors/immunology/*metabolism MH - Animals MH - Antibodies, Blocking/*administration & dosage MH - Antibodies, Monoclonal/*administration & dosage MH - Antibodies, Monoclonal, Humanized MH - Antineoplastic Agents/*administration & dosage MH - Body Weight/drug effects MH - Cachexia/etiology/*prevention & control MH - Cisplatin/administration & dosage MH - Colonic Neoplasms/*complications MH - Disease Models, Animal MH - Disease Progression MH - Everolimus/administration & dosage MH - Male MH - Mice MH - Mice, Inbred BALB C MH - TOR Serine-Threonine Kinases/metabolism MH - Tumor Burden/drug effects PMC - PMC4960708 OTO - NOTNLM OT - ActRII blockade OT - Cancer cachexia OT - Cisplatin OT - Combination OT - Everolimus EDAT- 2016/07/28 06:00 MHDA- 2017/10/24 06:00 PMCR- 2016/07/26 CRDT- 2016/07/28 06:00 PHST- 2016/05/21 00:00 [received] PHST- 2016/07/04 00:00 [accepted] PHST- 2016/07/28 06:00 [entrez] PHST- 2016/07/28 06:00 [pubmed] PHST- 2017/10/24 06:00 [medline] PHST- 2016/07/26 00:00 [pmc-release] AID - 98 [pii] AID - 10.1186/s13395-016-0098-2 [doi] PST - epublish SO - Skelet Muscle. 2016 Jul 26;6:26. doi: 10.1186/s13395-016-0098-2. eCollection 2016.