Combination therapy with anamorelin and a myostatin inhibitor is advantageous for cancer cachexia in a mouse model.

Abstract

Cancer cachexia is a multifactorial disease that causes continuous skeletal muscle wasting. Thereby, it seems to be a key determinant of cancer‐related death. Although anamorelin, a ghrelin receptor agonist, has been approved in Japan for the treatment of cachexia, few medical treatments for cancer cachexia are currently available. Myostatin (MSTN)/growth differentiation factor 8, which belongs to the transforming growth factor‐β family, is a negative regulator of skeletal muscle mass, and inhibition of MSTN signaling is expected to be a therapeutic target for muscle‐wasting diseases. Indeed, we have reported that peptide‐2, an MSTN‐inhibiting peptide from the MSTN prodomain, alleviates muscle wasting due to cancer cachexia. Herein, we evaluated the therapeutic benefit of myostatin inhibitory D‐peptide‐35 (MID‐35), whose stability and activity were more improved than those of peptide‐2 in cancer cachexia model mice. The biologic effects of MID‐35 were better than those of peptide‐2. Intramuscular administration of MID‐35 effectively alleviated skeletal muscle atrophy in cachexia model mice, and the combination therapy of MID‐35 with anamorelin increased food intake and maximized grip strength, resulting in longer survival. Our results suggest that this combination might be a novel therapeutic tool to suppress muscle wasting in cancer cachexia.