Many patients with cancer develop cachexia, characterized by anorexia and progressive loss of adipose tissue and skeletal muscle. However, the molecular mechanisms mediating cachexia remain poorly understood and no approved therapies exist. Writing in Nature Medicine, Allan and colleagues demonstrate that antibody-mediated antagonism of the receptor for growth differentiation factor 15 (GDF15) reverses cancer cachexia in mice.
GDF15 is a circulating protein that has been implicated in energy homeostasis and body weight regulation. Notably, circulating levels of GDF15 correlate with cachexia and reduced survival in patients with cancer. Studies in mice have indicated that GDF15-induced weight loss is mediated by a GDNF family receptor-α-like (GFRAL)-Ret proto-oncogene (RET) signalling complex in brainstem neurons, so Allan and colleagues set out to investigate GDF15–GFRAL–RET signalling inhibition as an approach to treating cancer cachexia.
The authors first generated a library of 100,000 hybridoma clones from mice immunized with the GFRAL extracellular domain. This enabled identification of the monoclonal antibody 3P10, which inhibited GDF15-induced signalling in cells co-expressing RET and GFRAL. Further analysis showed that 3P10 specifically interacted with GFRAL via the D3 domain, preventing RET recruitment to the GDF15–GFRAL complex.
In wild-type mice, subcutaneous injection of 3P10 blocked recombinant GDF15 (rGDF15)-induced signalling and brainstem neuronal activation, which altered body weight: a single dose of 3P10 prevented rGDF15-induced weight loss, and weekly administration of 3P10 accelerated the cumulative weight gain in mice on a high-fat diet.
Next, the authors investigated potential anticachectic effects of GFRAL inhibition. In multiple mouse cancer models (each exhibiting high levels of serum GDF15), subcutaneous injection of 3P10 prevented tumour-induced body-weight loss, preserving both adipose tissue and skeletal muscle. Furthermore, when 3P10 was administered to a human xenograft model after significant body weight loss, the mice gained back almost all of the lost weight.
The mechanism mediating GDF15-induced cachexia and its reversal by 3P10 in tumour-bearing mice was independent of food intake, and effects on lipolysis played a key role. Lipid oxidation was increased and glucose oxidation was reduced in tumour-bearing mice during their active weight-loss phase: effects that were reversed by 3P10. In addition, rGDF15 induced expression of genes involved in lipid metabolism in adipose tissues in wild-type mice, and GDF15-mediated weight loss was prevented in adipose triglyceride lipase-knockout mice. Furthermore, degeneration of adrenergic neurons in the peripheral sympathetic nervous system prior to GDF15 administration in mice prevented weight loss, indicating that the effect is dependent on the peripheral sympathetic nervous system.
Based on the promise of GFRAL inhibition as a novel strategy for the treatment of cancer cachexia, this approach is currently being investigated in phase I trials.
Nature Reviews Drug Discovery 19, 588 (2020)