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

  • Cell Metab. 2020 Dec 1;32(6):938-950.e6. doi: 10.1016/j.cmet.2020.10.023.
Danna M Breen  1 ,  Hanna Kim  2 ,  Donald Bennett  3 ,  Roberto A Calle  2 ,  Susie Collins  4 ,  Ryan M Esquejo  2 ,  Tao He  5 ,  Stephanie Joaquim  2 ,  Alison Joyce  6 ,  Matthew Lambert  5 ,  Laura Lin  5 ,  Betty Pettersen  7 ,  Shuxi Qiao  2 ,  Michelle Rossulek  2 ,  Gregory Weber  5 ,  Zhidan Wu  2 ,  Bei B Zhang  2 ,  Morris J Birnbaum  2
Affiliations
  • 1. Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA. Electronic address: [email protected].
  • 2. Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
  • 3. Biostatistics, Early Clinical Development, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
  • 4. Biostatistics, Early Clinical Development, Pfizer R&D UK Limited, Ramsgate Road, Sandwich, Kent, UK.
  • 5. Biomedicine Design, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
  • 6. Biomedicine Design, Pfizer Inc., 1 Burtt Road, Andover, MA, USA.
  • 7. Drug Safety Research and Development, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
PMID: 33207247 DOI: 10.1016/j.cmet.2020.10.023
Abstract

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.

Keywords
chemotherapy; cisplatin; emesis; growth differentiation factor 15; survival; weight loss.
Products