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. 2020 Dec 1;32(6):938-950.e6.
doi: 10.1016/j.cmet.2020.10.023. Epub 2020 Nov 17.

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

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
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Free article

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

Danna M Breen et al. Cell Metab. .
Free article

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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Conflict of interest statement

Declaration of Interests All authors are full-time employees of Pfizer Inc. D.B., M.J.B., R.A.C., B.P., and B.B.Z. are shareholders of Pfizer. M.R. has an immediate family member with management interests in Pfizer Inc. M.J.B. is a member of the Board of Directors of Cerevel. This manuscript relates to International Patent Application Publication No. WO2020/039321, which published February 27, 2020. Patent publication numbers US2020055930 and TW202021619 are both patent family members of the International Patent Application Publication No. WO2020/039321.

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