{"entity":{"id":"cachexia-biology","kind":"pathway","name":"Cancer cachexia","aka":[],"tldr":"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.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Cachexia","links":[{"label":"Groarke et al., Ponsegromab for the treatment of cancer cachexia (NEJM 2024)","url":"https://doi.org/10.1056/NEJMoa2409515"}],"tags":["mechanism"],"related":[],"cancers":["pancreatic","nsclc","gastric"],"sections":[],"technologies":["exercise-oncology","geriatric-assessment"],"targets":[],"drugs":[],"companies":[],"institutions":["fred-hutch","cold-spring-harbor","md-anderson"],"pathways":["jak-stat","inflammation-nfkb","cancer-metabolism"],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"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."],"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.","nodes":[{"id":"tum","label":"Tumour + inflammation","x":15,"y":50},{"id":"gdf","label":"GDF-15 → GFRAL (brainstem)","x":45,"y":25},{"id":"il6","label":"IL-6 / TNF / activin","x":45,"y":75},{"id":"app","label":"Anorexia","x":75,"y":25},{"id":"muscle","label":"Muscle proteolysis, fat lipolysis","x":75,"y":75},{"id":"out","label":"Weight loss, frailty, death","x":92,"y":50}],"edges":[{"from":"tum","to":"gdf","type":"activates"},{"from":"tum","to":"il6","type":"activates"},{"from":"gdf","to":"app","type":"activates"},{"from":"il6","to":"muscle","type":"activates"},{"from":"app","to":"out","type":"activates"},{"from":"muscle","to":"out","type":"activates"}],"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"]},"route":"/pathways/cachexia-biology/","neighbours":{"cancer":[{"id":"gastric","kind":"cancer","name":"Gastric & gastro-oesophageal junction cancer","route":"/cancers/gastric/"},{"id":"locally-advanced-pdac","kind":"cancer","name":"Locally advanced unresectable pancreatic ductal adenocarcinoma","route":"/cancers/locally-advanced-pdac/"},{"id":"metastatic-pdac","kind":"cancer","name":"Metastatic pancreatic ductal adenocarcinoma","route":"/cancers/metastatic-pdac/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"technology":[{"id":"cachexia-appetite-pharmacotherapy","kind":"technology","name":"Cachexia pharmacotherapy: GDF-15 blockade, anamorelin, olanzapine","route":"/technologies/cachexia-appetite-pharmacotherapy/"},{"id":"exercise-oncology","kind":"technology","name":"Exercise & lifestyle oncology","route":"/technologies/exercise-oncology/"},{"id":"geriatric-assessment","kind":"technology","name":"Geriatric assessment","route":"/technologies/geriatric-assessment/"},{"id":"resistance-training-cachexia","kind":"technology","name":"Resistance training and protein for cachexia and sarcopenia","route":"/technologies/resistance-training-cachexia/"}],"institution":[{"id":"cold-spring-harbor","kind":"institution","name":"Cold Spring Harbor Laboratory","route":"/institutions/cold-spring-harbor/"},{"id":"fred-hutch","kind":"institution","name":"Fred Hutchinson Cancer Center","route":"/institutions/fred-hutch/"},{"id":"md-anderson","kind":"institution","name":"MD Anderson Cancer Center","route":"/institutions/md-anderson/"}],"pathway":[{"id":"cancer-metabolism","kind":"pathway","name":"Cancer metabolism","route":"/pathways/cancer-metabolism/"},{"id":"inflammation-nfkb","kind":"pathway","name":"Inflammation & NF-κB","route":"/pathways/inflammation-nfkb/"},{"id":"jak-stat","kind":"pathway","name":"JAK-STAT signalling","route":"/pathways/jak-stat/"}],"idea":[{"id":"idea-cachexia-gdf15-prevention","kind":"idea","name":"Treat cachexia before it starts","route":"/ideas/idea-cachexia-gdf15-prevention/"}],"term":[{"id":"cachexia","kind":"term","name":"Cancer cachexia","route":"/terms/cachexia/"}],"trial":[{"id":"ponsegromab-phase-2","kind":"trial","name":"Ponsegromab phase 2 in cancer cachexia","route":"/trials/ponsegromab-phase-2/"},{"id":"romana-1-2","kind":"trial","name":"ROMANA 1 and ROMANA 2","route":"/trials/romana-1-2/"}]}}