{"entity":{"id":"idea-bio1-persister-metabolic-vulnerability","kind":"idea","name":"Starve the survivors: target the energy pathway drug-tolerant cells switch to","aka":[],"tldr":"Cells that survive treatment often change how they make energy, relying on burning fat rather than sugar. Blocking that switch might finish them off.","summary":"Drug-tolerant persisters and residual disease cells show increased oxidative phosphorylation and fatty acid oxidation dependence in melanoma, lung and leukaemia models. OXPHOS and fatty acid oxidation inhibitors have entered early clinical testing, with tolerability as the main issue. The proposal is intermittent, response-triggered administration at the point of maximal response rather than continuous use in bulk disease.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Acquired resistance to every therapy): Soria et al., Osimertinib in untreated EGFR-mutated NSCLC (FLAURA, NEJM 2018)","url":"https://doi.org/10.1056/NEJMoa1713137"}],"tags":[],"related":[],"cancers":["melanoma","aml"],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["mrd","resistance"],"trials":[],"people":[],"bottlenecks":["b-resistance","b-dormancy-mrd"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Metabolic inhibition applied at maximal response reduces measurable residual disease more than continuing targeted therapy alone, without the toxicity seen with continuous dosing.","rationale":"Metabolic state, unlike genotype, is shared across many persister populations, so the approach could apply across drivers; the failures of OXPHOS inhibitors to date have been in unselected bulk disease.","test":"Preclinical timing study comparing continuous versus nadir-triggered metabolic inhibition, then a phase 1b in patients in deep response with ctDNA as the pharmacodynamic endpoint.","maturity":"preclinical-evidence","actor":"research","cost":"medium","horizonYears":6},"route":"/ideas/idea-bio1-persister-metabolic-vulnerability/","neighbours":{"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"}],"term":[{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"mrd","kind":"term","name":"Minimal / molecular residual disease (MRD)","route":"/terms/mrd/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-dormancy-mrd","kind":"bottleneck","name":"Dormant cells and minimal residual disease","route":"/bottlenecks/b-dormancy-mrd/"}]}}