Cancer cachexia
The wasting syndrome that kills up to a third of cancer patients: tumours send hormonal signals (GDF-15, IL-6) that switch off appetite and burn muscle and fat. The first drug to reverse it, ponsegromab, showed weight gain in 2024.
Tumour- and host-derived GDF-15 acts on the brainstem GFRAL receptor to suppress appetite; IL-6/STAT3, TNF, activin/myostatin, and glucocorticoids drive muscle proteolysis (ubiquitin-proteasome, autophagy) and adipose lipolysis/browning. Cachexia worsens treatment tolerance and is largely irreversible late. Ponsegromab (anti-GDF-15, Pfizer) increased weight and activity in a phase 2 trial (NEJM 2024) and is in phase 3; anamorelin (ghrelin agonist) is approved in Japan; nutrition and exercise remain foundational. Cachexia is now treated as a target in its own right rather than an inevitability.
In one picture
A thermostat hijacked by the tumour: it tells the body it is full when it is starving and orders the furnace to burn muscle for fuel. Ponsegromab cuts the wire to the thermostat.
Diagram
top- Ponsegromab (anti-GDF-15) phase 3
- Anamorelin (approved Japan), olanzapine for appetite, corticosteroids short term
- Exercise and nutrition support (ESPEN/ASCO guidelines)
- Anti-IL-6 and activin/myostatin agents in trials
Notes
top- Leading programmes: Janowitz (CSHL) on cachexia mechanisms; Fearon legacy (Edinburgh) on definitions; Roeland (Oregon) and Baracos (Alberta) on clinical cachexia; Pfizer ponsegromab programme; Cancer Grand Challenges CANCAN team.