An antibody blocking GRFAL–RET binding blunted GDF15-induced cachexia, preventing weight loss.
Major Finding: An antibody blocking GRFAL–RET binding blunted GDF15-induced cachexia, preventing weight loss.
Concept: GDF15 altered metabolism and led to aberrant sympathetic nervous system activity to cause cachexia.
Impact: This work debuts a therapeutic antibody of interest in treating cachexia and reveals its mechanism.
Elevated levels of the cytokine growth differentiation factor 15 (GDF15) have been linked to cachexia and poorer survival in patients with cancer. Recent evidence indicates that GDF15 binding to the cell-surface receptor GDNF family receptor α–like (GFRAL), which triggers oligomerization with the receptor tyrosine kinase RET and consequent RET signaling, underlies the connection between GDF15 and cachexia. Based on these findings, Suriben, Chen, Higbee, and colleagues developed the GFRAL-targeting monoclonal antibody 3P10. In vitro, treatment with this high-affinity antibody did not disrupt GDF15–GFRAL binding, but instead blocked GFRAL–RET binding to inhibit GDF15-induced RET signaling. In vivo, 3P10 administration prevented weight loss induced by recombinant GDF15 and in mouse cancer models with highly GDF15-secreting tumors. This effect was not simply due to prevention of anorexia, as tumor-bearing mice on calorie-restricted diets also exhibited a reduction in body-weight loss. Alternatively, 3P10 treatment increased glucose oxidation and reduced lipid oxidation in tumor-bearing mice, bringing lipid- and glucose-oxidation levels closer to those of tumor-free mice. Notably, recombinant GDF15 induced expression of Pnpla2, encoding adipose triglyceride lipase (ATGL), and Pnpla2 knockout prevented GDF15-induced weight loss without blunting anorexia and blocked the pathologic decrease in glucose oxidation and increase in lipid oxidation observed in GDF15-treated Pnpla2–wild-type mice. Additionally, chemical ablation of adrenergic neurons in the peripheral sympathetic nervous system did not prevent GDF15-induced reduction in food intake, but still substantially reduced weight loss, indicating a role for the sympathetic nervous system in GDF15-mediated cachexia. In summary, this work describes a novel therapeutic antibody that is worth investigating further—and is currently in clinical trials—for the treatment of cachexia and elucidates previously unknown mechanisms by which GDF15 causes food intake–independent weight loss.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.