1. Academic Validation
  2. 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: danna.breen@pfizer.com.
  • 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.
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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