2. Academic Validation
  3. GDF-15 Neutralization Alleviates Platinum-Based Chemotherapy-Induced Emesis, Anorexia, and Weight Loss in Mice and Nonhuman Primates

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

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.

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