ideasIdea
Starve MYC-driven tumours by blocking protein production machinery
Cancers driven by MYC need to make proteins at an unusually fast rate. Slowing the cell's protein factory hits them harder than it hits normal cells.
MYC amplification imposes dependence on cap-dependent translation, ribosome biogenesis and eIF4A/eIF4E activity. Selective eIF4A inhibitors (for example zotatifin) and RNA polymerase I inhibitors have entered clinical trials. Rather than treating these as broad cytotoxics, the proposal is to select patients by MYC amplification or a translation-dependency signature, which has not been done systematically.
Hypothesis
Response to eIF4A or ribosome biogenesis inhibition is concentrated in tumours with MYC amplification or a high translation-dependency signature, with a response rate at least three times that of unselected patients.
Rationale
Blocking translation is an indirect route to MYC that requires no MYC binder; the dependency is well supported in models, but trials to date have largely been unselected, which is a common reason such drugs fail.
What would test it
Biomarker-stratified phase 2 with pre-specified MYC-amplified and signature-high cohorts, powered to compare response rates between strata.
Maturity
early clinical
Who has to act
industry
Cost to try
Medium ($1M to $50M)
Years to first evidence
4
Bottlenecks it attacks
- The undruggable drivers · The proteins that drive most cancers, such as MYC, mutant p53 and most RAS variants, still have no good drug.
- Biomarkers are not validated or standardised · Tests that decide who gets a drug are often not validated prospectively and are measured differently in every lab.