Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer
Year: 2022
Type: article
Abstract: 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.
Source: Nature Communications
Authors: Andre Lima Queiroz, Ezequiel Dantas, Shakti Ramsamooj, Anirudh Murthy, Mujmmail Ahmed, Elizabeth R. M. Zunica, Roger J. Liang, Jessica Murphy, Corey D. Holman, Curtis J. Bare, Gregory Ghahramani, Zhidan Wu, David E. Cohen, John P. Kirwan, Lewis C. Cantley, Christopher L. Axelrod, Marcus D. Goncalves
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,890
Funders: U.S. Department of Health and Human Services, American Association for Cancer Research, Pfizer, AstraZeneca, Vanderbilt University, Lung Cancer Research Foundation, Vanderbilt University Medical Center, Louisiana Clinical and Translational Science Center, National Institutes of Health, Weill Cornell Medical College, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Complementary and Integrative Health
Awards: G1221739687, G1805704937, G3143440274, The Role of Hypoketonemia in the Cancer Anorexia-Cachexia Syndrome, G3667826151, Vanderbilt Mouse Metabolic Phenotyping Center, G4424950377, G5850863802, G7018334597, Botanical Approaches to Combat Metabolic Syndrome, G9000052735, G9000311072, Cancer Center Support Grant, Role of Phosphoinositides and Protein Kinases in the control of Cancer Metabolism, Louisiana Clinical and Translational Science Center, Vanderbilt Diabetes Research Center
OpenAlex ID: W4290659783