OnCo
ideasIdea

Break up the liquid droplets where oncogenic transcription happens

Some cancer-driving proteins gather into droplet-like blobs inside the nucleus to switch genes on. Drugs that dissolve those blobs might switch the cancer programme off.

Transcriptional condensates concentrate MYC, fusion oncoproteins, mediator complex and RNA polymerase at super-enhancers. Certain drugs, including some antineoplastics, concentrate selectively in condensates, and condensate-modulating chemotypes have been reported. A dedicated screen using condensate-specific reporters (optoDroplet or in vitro reconstitution with labelled scaffolds) could identify compounds that selectively dissolve oncogenic condensates while sparing normal ones.

Hypothesis
Compounds that dissolve oncoprotein condensates suppress super-enhancer-driven transcription and kill condensate-dependent tumour cells at concentrations that do not affect housekeeping transcription.
Rationale
Condensate biology is a general mechanism for transcription factors that lack pockets, and drug partitioning into condensates has been shown to affect potency, so the physics is at least addressable.
What would test it
Reconstituted condensate screens with orthogonal cellular validation in an EWS-FLI1 and a MYC-amplified model, with transcriptomic evidence of selective super-enhancer target loss.
Maturity
speculative
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
9
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.

Connected

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