OnCo
ideasIdea

Kill the sleeping survivor cells with iron-dependent cell death

A few cancer cells survive treatment by going quiet rather than mutating. These survivors are unusually vulnerable to a particular kind of cell death, which a drug could trigger.

Drug-tolerant persister cells adopt a mesenchymal, slow-cycling state that depends on the lipid peroxidase GPX4; their elimination by GPX4 inhibition has been shown in several models across lung, breast and other cancers. Translating this requires a tolerable GPX4 inhibitor or an alternative ferroptosis inducer, and a schedule that applies it during the persister window shortly after maximal response.

Hypothesis
Ferroptosis induction timed to the persister window after maximal response to targeted therapy reduces residual disease and delays regrowth in vivo compared with continued targeted therapy alone.
Rationale
Persisters are the reservoir from which genetic resistance later emerges; eliminating them attacks resistance before mutations arise, and the vulnerability is a state rather than a genotype, so it applies across drivers.
What would test it
In vivo studies in three driver-defined models comparing scheduled ferroptosis induction at nadir with continuous therapy, measuring residual cell number and time to regrowth.
Maturity
preclinical evidence
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
6
Bottlenecks it attacks

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