Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer.

Autor: Queiroz AL; Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA., Dantas E; Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA., Ramsamooj S; Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA., Murthy A; Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA., Ahmed M; Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA., Zunica ERM; Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA., Liang RJ; Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA.; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA., Murphy J; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA.; Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Holman CD; Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA., Bare CJ; Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA., Ghahramani G; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, 10065, USA., Wu Z; Internal Medicine Research Unit, Pfizer Global R&D, Cambridge, MA, USA., Cohen DE; Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA., Kirwan JP; Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA., Cantley LC; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA., Axelrod CL; Pennington Biomedical Research Center, Baton Rouge, LA, 70808, USA., Goncalves MD; Division of Endocrinology, Department of Medicine, Weill Cornell Medicine, New York, NY, 10065, USA. mdg9010@med.cornell.edu.; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, 10065, USA. mdg9010@med.cornell.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Aug 08; Vol. 13 (1), pp. 4633. Date of Electronic Publication: 2022 Aug 08.
DOI: 10.1038/s41467-022-32135-0
Abstrakt: Cancer cachexia is a common, debilitating condition with limited therapeutic options. Using an established mouse model of lung cancer, we find that cachexia is characterized by reduced food intake, spontaneous activity, and energy expenditure accompanied by muscle metabolic dysfunction and atrophy. We identify Activin A as a purported driver of cachexia and treat with ActRIIB-Fc, a decoy ligand for TGF-β/activin family members, together with anamorelin (Ana), a ghrelin receptor agonist, to reverse muscle dysfunction and anorexia, respectively. Ana effectively increases food intake but only the combination of drugs increases lean mass, restores spontaneous activity, and improves overall survival. These beneficial effects are limited to female mice and are dependent on ovarian function. In agreement, high expression of Activin A in human lung adenocarcinoma correlates with unfavorable prognosis only in female patients, despite similar expression levels in both sexes. This study suggests that multimodal, sex-specific, therapies are needed to reverse cachexia.
(© 2022. The Author(s).)
Databáze: MEDLINE
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