美国Takeda生物制药公司Bernard B. Allan等研究人员发现，抗体介导的GDF15-GFRAL活性抑制可逆转小鼠癌症恶病质。这一研究成果于2020年7月13日在线发表在国际学术期刊《自然—医学》上。
Title: Antibody-mediated inhibition of GDF15–GFRAL activity reverses cancer cachexia in mice
Author: Rowena Suriben, Michael Chen, Jared Higbee, Julie Oeffinger, Richard Ventura, Betty Li, Kalyani Mondal, Zhengyu Gao, Dina Ayupova, Pranali Taskar, Diana Li, Shelley R. Starck, Hung-I Harry Chen, Michele McEntee, Subhash D. Katewa, Van Phung, Marilyn Wang, Avantika Kekatpure, Damodharan Lakshminarasimhan, Andre White, Andrea Olland, Raj Haldankar, Mark J. Solloway, Jer-Yuan Hsu, Yan Wang, Jie Tang, Darrin A. Lindhout, Bernard B. Allan
Abstract: Cancer cachexia is a highly prevalent condition associated with poor quality of life and reduced survival1. Tumor-induced perturbations in the endocrine, immune and nervous systems drive anorexia and catabolic changes in adipose tissue and skeletal muscle, hallmarks of cancer cachexia2,3,4. However, the molecular mechanisms driving cachexia remain poorly defined, and there are currently no approved drugs for the condition. Elevation in circulating growth differentiation factor 15 (GDF15) correlates with cachexia and reduced survival in patients with cancer5,6,7,8, and a GDNF family receptor alpha like (GFRAL)–Ret proto-oncogene (RET) signaling complex in brainstem neurons that mediates GDF15-induced weight loss in mice has recently been described9,10,11,12. Here we report a therapeutic antagonistic monoclonal antibody, 3P10, that targets GFRAL and inhibits RET signaling by preventing the GDF15-driven interaction of RET with GFRAL on the cell surface. Treatment with 3P10 reverses excessive lipid oxidation in tumor-bearing mice and prevents cancer cachexia, even under calorie-restricted conditions. Mechanistically, activation of the GFRAL–RET pathway induces expression of genes involved in lipid metabolism in adipose tissues, and both peripheral chemical sympathectomy and loss of adipose triglyceride lipase protect mice from GDF15-induced weight loss. These data uncover a peripheral sympathetic axis by which GDF15 elicits a lipolytic response in adipose tissue independently of anorexia, leading to reduced adipose and muscle mass and function in tumor-bearing mice.