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

被引：108

作者：

Breen, Danna M. ^{[1
]}

Kim, Hanna ^{[1
]}

Bennett, Donald ^{[2
]}

Calle, Roberto A. ^{[1
]}

Collins, Susie ^{[3
]}

Esquejo, Ryan M. ^{[1
]}

He, Tao ^{[4
]}

Joaquim, Stephanie ^{[1
]}

Joyce, Alison ^{[5
]}

Lambert, Matthew ^{[4
]}

Lin, Laura ^{[4
]}

Pettersen, Betty ^{[6
]}

Qiao, Shuxi ^{[1
]}

Rossulek, Michelle ^{[1
]}

Weber, Gregory ^{[4
]}

Wu, Zhidan ^{[1
]}

Zhang, Bei B. ^{[1
]}

Birnbaum, Morris J. ^{[1
]}

机构：

[1] Pfizer Inc, Internal Med Res Unit, 1 Portland St, Cambridge, MA USA

[2] Pfizer Inc, Early Clin Dev, Biostat, 1 Portland St, Cambridge, MA USA

[3] Pfizer R&D UK Ltd, Early Clin Dev, Biostat, Ramsgate Rd, Sandwich, Kent, England

[4] Pfizer Inc, Biomed Design, 1 Portland St, Cambridge, MA USA

[5] Pfizer Inc, Biomed Design, 1 Burtt Rd, Andover, MA USA

[6] Pfizer Inc, Drug Safety Res & Dev, 1 Portland St, Cambridge, MA USA

来源：

CELL METABOLISM | 2020年 / 32卷 / 06期

关键词：

DIFFERENTIATION FACTOR 15; MACROPHAGE INHIBITORY CYTOKINE-1; CELL LUNG-CANCER; BREAST-CANCER; LIQUID-CHROMATOGRAPHY; MULTIPLE BIOMARKERS; INDUCED NAUSEA; CISPLATIN; DOXORUBICIN; TOXICITY;

D O I：

10.1016/j.cmet.2020.10.023

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：938 / 950.e6

页数：20

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