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

Abstract The cancer anorexia-cachexia syndrome (CACS) is a common, debilitating condition with limited therapeutic options. The defining feature of CACS is weight loss, which suggests a state of negative energy balance. It is unclear whether this net reduction in energy is due solely to anorexia or if a combination of anorexia and increased energy expenditure (EE) occurs. To address this question, we induced lung cancer in mice and measured changes in food intake, EE, and body composition. Mice with CACS developed reductions in food intake, spontaneous activity, and EE. There was severe atrophy and markers of metabolic dysfunction in the adipose and skeletal muscle tissues as compared to mice without CACS and pair-fed wild-type mice. We used anamorelin fumarate (Ana), a ghrelin receptor agonist, alone or in combination ActRIIB-Fc, a ligand trap for TGF-β/activin family members, to reverse anorexia and skeletal muscle atrophy, respectively. Ana effectively increased food intake and the combination of drugs increased lean mass, restored spontaneous activity, and improved overall survival. These beneficial effects were limited to female mice. Our findings suggest that multimodal, gender-specific, therapies are needed to reverse CACS.