# Cancer cachexia

Source: https://onco.cc/pathways/cachexia-biology/  
OnCo record `cachexia-biology` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-08
- Tags: mechanism
- Analogy: 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.
- Interventions: 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

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Cachexia
- Groarke et al., Ponsegromab for the treatment of cancer cachexia (NEJM 2024): https://doi.org/10.1056/NEJMoa2409515

## Connected records

- cancers: [Gastric & gastro-oesophageal junction cancer](https://onco.cc/cancers/gastric/), [Locally advanced unresectable pancreatic ductal adenocarcinoma](https://onco.cc/cancers/locally-advanced-pdac/), [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [Cachexia pharmacotherapy: GDF-15 blockade, anamorelin, olanzapine](https://onco.cc/technologies/cachexia-appetite-pharmacotherapy/), [Exercise & lifestyle oncology](https://onco.cc/technologies/exercise-oncology/), [Geriatric assessment](https://onco.cc/technologies/geriatric-assessment/), [Resistance training and protein for cachexia and sarcopenia](https://onco.cc/technologies/resistance-training-cachexia/)
- institutions: [Cold Spring Harbor Laboratory](https://onco.cc/institutions/cold-spring-harbor/), [Fred Hutchinson Cancer Center](https://onco.cc/institutions/fred-hutch/), [MD Anderson Cancer Center](https://onco.cc/institutions/md-anderson/)
- pathways: [Cancer metabolism](https://onco.cc/pathways/cancer-metabolism/), [Inflammation & NF-κB](https://onco.cc/pathways/inflammation-nfkb/), [JAK-STAT signalling](https://onco.cc/pathways/jak-stat/)
- ideas: [Treat cachexia before it starts](https://onco.cc/ideas/idea-cachexia-gdf15-prevention/)
- terms: [Cancer cachexia](https://onco.cc/terms/cachexia/)
- trials: [Ponsegromab phase 2 in cancer cachexia](https://onco.cc/trials/ponsegromab-phase-2/), [ROMANA 1 and ROMANA 2](https://onco.cc/trials/romana-1-2/)

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