title: ActRII blockade protects mice from cancer cachexia and prolongs survival in the presence of anti-cancer treatments.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Shinji
authors.identifier: 0000-0002-0166-2773
authors.initials: S
authors.lastname: Hatakeyama
authors.affiliation: MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Serge
authors.initials: S
authors.lastname: Summermatter
authors.affiliation: MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Marie
authors.initials: M
authors.lastname: Jourdain
authors.affiliation: MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Melly
authors.affiliation: MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Giulia C
authors.initials: GC
authors.lastname: Minetti
authors.affiliation: MusculoSkeletal Diseases, Novartis Institutes for Biomedical Research, Novartis Pharma AG, CH-4002 Basel, Switzerland.
authors.forename: Estelle
authors.initials: E
authors.lastname: Lach-Trifilieff
mesh_terms: D030301:Activin Receptors, Type II / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001835:Body Weight / Q000187:drug effects; D002100:Cachexia / Q000209:etiology / Q000517:prevention & control*; D002945:Cisplatin / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000150:complications*; D004195:Disease Models, Animal; D018450:Disease Progression; D000068338:Everolimus / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000068338:Everolimus; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D030301:Activin Receptors, Type II; C425585:activin receptor type II-A; C000596367:bimagrumab; D002945:Cisplatin
keywords: ActRII blockade; Cancer cachexia; Cisplatin; Combination; Everolimus