Preclinical models of cancer cachexia: Bridging the gap to clinical applications

Cancer cachexia (CC) is a multifactorial syndrome affecting up to 80% of advanced cancer patients. Characterized by unintentional weight loss, skeletal muscle wasting, and fat depletion, CC significantly impairs quality of life, treatment tolerance, and patient survival. Despite its prevalence, effective therapeutic options remain limited, underscoring the urgent need for preclinical models that closely mimic clinical symptoms to support drug development. Towards this end, we developed and validated a CC preclinical model with HT-1080 xenograft in NCG mice, which demonstrated hallmark CC features, including body weight loss, fat and muscle loss, as well as impaired physical performance. The tumor-bearing mice also displayed elevated hGDF15 levels (undetectable in non-tumor-bearing (NTB) mice), and significantly reduced cumulative food intake. In this study, we used Ponsegromab (anti-GDF15 monoclonal antibody) as a positive treatment for CC starting when mice had lost ~7% body weight. At the end of the study, mice in hIgG1-treated control group suffered over 15% body weight loss, while the Ponsegromab treatment restored body weight to baseline levels. Although Ponsegromab treated mice remained lighter than NTB PBS controls, our data suggested that Ponsegromab treatment could significantly improve food intake and increase survival rates. Fat and muscle tissue weights, including gonadal, peri-renal, and inguinal subscapular white fat, as well as gastrocnemius and soleus muscles, were significantly reduced in the hIgG1-treated control group compared to baseline controls. Ponsegromab treatment preserved fat and muscle weights to levels similar to the baseline group. Motor function assessed via rotarod performance, and grip strength showed coordination and strength impairments in tumor-bearing mice, while Ponsegromab significantly improved grip strength and physical performance in comparison to the hIgG1-treated control group. In conclusion, our validated preclinical cachexia models closely align with clinical CC manifestations, providing a robust platform for the evaluation of novel therapeutic strategies. These models enable detailed exploration of CC mechanisms and support the development of effective interventions to mitigate cachexia and improve patient outcomes.