OnCo
ideasIdea

Attack extrachromosomal DNA, the engine of oncogene amplification

Many aggressive tumours keep their cancer genes on free-floating DNA circles that let them dial resistance up and down at will. Drugs that break the circles or the cell's tolerance of them are a new frontier.

ecDNA carries EGFR, MYC, MDM2, and CDK4 amplicons in glioblastoma, sarcoma, and gastric cancer, associates with poor survival, and enables rapid drug resistance by copy-number fluctuation. The eDyNAmiC Cancer Grand Challenge team reported CHK1 dependence and transcriptionreplication conflicts in ecDNA+ cells (2024).

Hypothesis
ecDNA-positive tumours are selectively sensitive to CHK1 inhibition combined with the amplified-oncogene inhibitor, and ecDNA status detectable by WGS or cfDNA identifies responders.
Rationale
Preclinical CHK1 sensitivity, an ecDNA detection assay (AmpliconArchitect) applicable to routine WGS, and the failure of oncogene inhibitors alone in ecDNA-driven tumours.
What would test it
Phase 1/2 of a CHK1 inhibitor plus targeted agent in ecDNA-positive EGFR-amplified glioblastoma and MDM2/CDK4-amplified sarcoma, with ecDNA burden in cfDNA as a pharmacodynamic marker.
Maturity
preclinical evidence

Connected

12top

Pages like this

not linked directly; found by shared links