In mice and nonhuman primates, a GDF-15 antibody blocked platinum-based chemotherapy side effects.
Major Finding: In mice and nonhuman primates, a GDF-15 antibody blocked platinum-based chemotherapy side effects.
Concept: GDF-15 is a GRFAL-binding cytokine that is elevated by platinum-based drugs in patients with cancer.
Impact: This work suggests that GDF-15–GRFAL blockade may be of use for ameliorating platinum side effects.
Nausea, emesis, anorexia, and weight loss are notorious dose-limiting side effects of platinum-based chemotherapies, but little is known about the origins of these deleterious effects, and currently available treatments are not fully effective. Recently, growth differentiation 15 (GDF-15), a cytokine that activates the receptor GDNF family receptor α-like (GRFAL) in the hindbrain, has emerged as a potential mediator of these side effects of platinum-based chemotherapy. To investigate this, Breen and colleagues first established that serum GDF-15 levels were higher in patients with non–small cell lung cancer (NSCLC), colorectal cancer, or ovarian cancer treated with platinum-based chemotherapy compared with patients with the same tumor types treated with non–platinum-based chemotherapy and healthy controls. In wild-type mice, Gdf15 (encoding GDF-15) knockout markedly reduced the anorexia and weight loss associated with cisplatin, oxaliplatin, or carboplatin treatment. Further, mice engineered to overexpress recombinant human GDF-15 exhibited weight loss that was reversible via treatment with a monoclonal antibody to human GDF-15, mAB1. Additionally, in nonhuman primates (cynomolgus monkeys) treated with cisplatin, circulating free GDF-15 levels increased within four hours and remained elevated over the 11-day study period, whereas monkeys pretreated with mAB1 showed no such increase in serum GDF-15. Pretreatment with mAB1 also increased food intake and decreased emesis in monkeys treated with cisplatin, consistent with the results in mice, although the study period was not long enough to evaluate body-weight changes. Notably, mAB1 was also able to reduce mouse GDF-15 levels in vivo, and mice bearing NSCLC xenograft tumors treated with mAB1 and cisplatin had lower weight loss and improved overall survival compared with control mice treated with cisplatin alone. Collectively, these findings indicate that GDF-15–GRFAL blockade may be a strategy of interest to reduce emesis and weight loss in patients with cancer treated with platinum-based chemotherapies.
Breen DM, Kim H, Bennett D, Calle RA, Collins S, Esquejo RM, et al. GDF-15 neutralization alleviates platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and nonhuman primates. Cell Metab 2020;32:938–50.E6.
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