ideasIdea
Degraders for the fusion proteins that drive childhood sarcomas
Some sarcomas in children are caused by two genes fused into one abnormal protein. That protein is the whole disease, but no drug binds it. Destroying it instead of blocking it could work.
EWS-FLI1 in Ewing sarcoma and PAX3-FOXO1 in alveolar rhabdomyosarcoma are single, tumour-specific, genetically validated drivers with no enzymatic activity. Degradation via recruited E3 ligases, or indirect destabilisation through their obligate cofactors (for example BRD9 in the ncBAF complex for synovial sarcoma, already showing clinical activity with BRD9 degraders), offers a route. Their absence from normal tissue means an unusually wide therapeutic index.
Hypothesis
A degrader that lowers fusion protein levels by 70 percent causes tumour regression in patient-derived fusion-positive sarcoma models, with no effect on fusion-negative controls.
Rationale
The BRD9 degrader experience in synovial sarcoma shows that attacking a complex member of a fusion-driven transcriptional programme is clinically tractable; fusion drivers are the cleanest targets in oncology if a modality can reach them.
What would test it
Parallel degrader campaigns against the fusion proteins and their obligate cofactors, prioritised by CRISPR dependency data, then testing in paediatric PDX panels with the Paediatric Preclinical Testing Consortium.
Maturity
preclinical evidence
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
7
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.
- Rare and paediatric cancers without markets · Taken together rare cancers are a fifth of all cancers, but each one alone is too small for a company to invest in.