Kim-Muller Ja Young, Song LouJin, LaCarubba Paulhus Brianna, Pashos Evanthia, Li Xiangping, Rinaldi Anthony, Joaquim Stephanie, Stansfield John C, Zhang Jiangwei, Robertson Andrew, Pang Jincheng, Opsahl Alan, Boucher Magalie, Breen Danna, Hales Katherine, Sheikh Abdul, Wu Zhidan, Zhang Bei B
Internal Medicine Research Unit, Pfizer Worldwide Research, Development & Medical, 1 Portland St., Cambridge, MA, USA.
Biostatistics, Early Clinical Development, Pfizer Worldwide Research, Development & Medical, 1 Portland St., Cambridge, MA, USA.
Cell Rep. 2023 Jan 31;42(1):111947. doi: 10.1016/j.celrep.2022.111947. Epub 2023 Jan 10.
Cancer cachexia is a disorder characterized by involuntary weight loss and impaired physical performance. Decline in physical performance of patients with cachexia is associated with poor quality of life, and currently there are no effective pharmacological interventions that restore physical performance. Here we examine the effect of GDF15 neutralization in a mouse model of cancer-induced cachexia (TOV21G) that manifests weight loss and muscle function impairments. With comprehensive assessments, our results demonstrate that cachectic mice treated with the anti-GDF15 antibody mAB2 exhibit body weight gain with near-complete restoration of muscle mass and markedly improved muscle function and physical performance. Mechanistically, the improvements induced by GDF15 neutralization are primarily attributed to increased caloric intake, while altered gene expression in cachectic muscles is restored in caloric-intake-dependent and -independent manners. The findings indicate potential of GDF15 neutralization as an effective therapy to enhance physical performance of patients with cachexia.
癌症恶病质是一种以非自愿体重减轻和身体机能受损为特征的病症。恶病质患者身体机能的下降与生活质量差相关，目前尚无有效的药物干预措施来恢复身体机能。在此，我们研究了在表现出体重减轻和肌肉功能受损的癌症诱导恶病质小鼠模型（TOV21G）中中和生长分化因子15（GDF15）的效果。通过全面评估，我们的结果表明，用抗GDF15抗体mAB2治疗的恶病质小鼠体重增加，肌肉质量几乎完全恢复，肌肉功能和身体机能显著改善。从机制上讲，GDF15中和诱导的改善主要归因于热量摄入增加，而恶病质肌肉中改变的基因表达以热量摄入依赖和非依赖的方式恢复。这些发现表明，中和GDF15作为一种有效疗法来提高恶病质患者身体机能具有潜力。
