Advanced High-Content Phenotypic Screening to Identify Drugs That Ameliorate the Inhibition of Skeletal Muscle Cell Differentiation Induced by Cancer Cachexia Serum

Background/Objectives: Cancer cachexia (CC) is a prevalent and debilitating syndrome in cancer patients, characterized by severe muscle and weight loss, leading to increased mortality and reduced quality of life. Despite the significant impact, effective treatments are lacking due to an incomplete understanding of its underlying mechanisms. In this study, we aim to develop drugs that ameliorate the inhibition of muscle differentiation induced by CC. We established an advanced, high-content phenotypic screening system using the serum of cancer patients and identified potential compounds. Methods: We used cancer patients’ sera as pathophysiological stimuli in our screening system to evaluate their effects on muscle atrophy and differentiation. Various histone deacetylase (HDAC) inhibitors were tested for their efficacy. The system’s translational relevance was validated by comparing results with clinical data and in vivo cachexia models. Results: Using our screening system, we evaluated several cancer patients’ sera and found that they reflect clinical features of cancer cachexia. In addition, HDAC inhibitors, particularly those with broad-spectrum inhibition, showed promise as agents to ameliorate the inhibition of muscle differentiation induced by CC sera. This system’s findings were consistent with clinical and in vivo data, highlighting its potential for identifying new drugs. Conclusions: The high-content phenotypic screening system effectively mimics some key aspects of CC pathophysiology on skeletal muscle, providing a valuable tool for drug discovery and understanding CC mechanisms. The translational relevance of our system offers a promising avenue for therapeutic advancements in the management of cancer cachexia, with the potential to improve patient outcomes and quality of life.