GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates

• Published in: Cell metabolism Vol. 32; no. 6; pp. 938 - 950.e6
• Main Authors: Breen, Danna M., Kim, Hanna, Bennett, Donald, Calle, Roberto A., Collins, Susie, Esquejo, Ryan M., He, Tao, Joaquim, Stephanie, Joyce, Alison, Lambert, Matthew, Lin, Laura, Pettersen, Betty, Qiao, Shuxi, Rossulek, Michelle, Weber, Gregory, Wu, Zhidan, Zhang, Bei B., Birnbaum, Morris J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2020
• Subjects: chemotherapy; cisplatin; emesis; growth differentiation factor 15; survival; weight loss; weight loss; emesis; cisplatin; growth differentiation factor 15; chemotherapy; survival
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2020.10.023

Platinum-based cancer therapy is restricted by dose-limiting side effects and is associated with elevation of growth differentiation factor 15 (GDF-15). But whether this elevation contributes to such side effects has been unclear. Here, we explored the effects of GDF-15 blockade on platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and/or nonhuman primate models. We found that circulating GDF-15 is higher in subjects with cancer receiving platinum-based chemotherapy and is positively associated with weight loss in colorectal cancer (NCT00609622). Further, chemotherapy agents associated with high clinical emetic score induce circulating GDF-15 and weight loss in mice. Platinum-based treatment-induced anorexia and weight loss are attenuated in GDF-15 knockout mice, while GDF-15 neutralization with the monoclonal antibody mAB1 improves survival. In nonhuman primates, mAB1 treatment attenuates anorexia and emesis. These results suggest that GDF-15 neutralization is a potential therapeutic approach to alleviate chemotherapy-induced side effects and improve the quality of life. [Display omitted] •Plasma GDF-15 is higher in subjects with cancer receiving platinum-based chemotherapy•GDF-15 deletion attenuates anorexia and weight loss induced by platinum-based agents•GDF-15 neutralization lowered cisplatin-induced emesis/anorexia in nonhuman primates•GDF-15 neutralization + cisplatin treatment promotes survival in a mouse tumor model In this work, circulating GDF-15 is higher in subjects with cancer receiving platinum-based chemotherapy. In mice and/or nonhuman primates, GDF-15 neutralization with a novel antibody (mAB1) alleviates emesis, anorexia, and weight loss induced by platinum-based chemotherapies, and mAB1 treatment improves survival in tumor-bearing mice when given in combination with cisplatin.