ideasIdea
Block the recycling that keeps dormant cells alive
Sleeping cancer cells survive by recycling their own contents. An old malaria drug blocks that recycling and is being tested in people with no visible cancer but detectable residual cells.
Dormant disseminated cells depend on autophagy for survival, and hydroxychloroquine plus mTOR inhibition has been tested in bone-marrow-positive breast cancer survivors in the CLEVER-type design at Johns Hopkins. The concept is attractive because it treats survivors while disease burden is at its minimum, but hydroxychloroquine is a weak, non-specific autophagy inhibitor; a potent selective ULK1 or ATG7 inhibitor would be the real test.
Hypothesis
Selective autophagy inhibition clears bone-marrow disseminated tumour cells or converts ctDNA-positive survivors to ctDNA-negative at a materially higher rate than observation.
Rationale
Autophagy dependence is a well-documented feature of quiescent, nutrient-poor cells, and dormancy is the setting where selective vulnerability should be largest. The endpoint is molecular and cheap, so a small trial can give a clear answer.
What would test it
A randomised phase 2 in ctDNA-positive or marrow-positive survivors comparing selective autophagy inhibition with observation, primary endpoint molecular clearance at 12 months, with serial marrow and plasma sampling.
Maturity
early clinical
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
5
Bottlenecks it attacks
- Dormant cells and minimal residual disease · After a 'successful' treatment, cells can sleep for years then relapse. We can barely detect them and cannot target them.
- No incentive to repurpose cheap drugs · Old, cheap drugs with anti-cancer signals never get the trials they need because no one profits from the result.