# Degraders for the fusion proteins that drive childhood sarcomas

Source: https://onco.cc/ideas/idea-bio1-fusion-tf-degraders/  
OnCo record `idea-bio1-fusion-tf-degraders` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed test: 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
- Actor: research

## Sources

- Bottleneck evidence (The undruggable drivers): Dang et al., Drugging the 'undruggable' cancer targets (Nature Reviews Cancer 2017): https://doi.org/10.1038/nrc.2017.36

## Connected records

- cancers: [Sarcomas (soft tissue, bone, GIST)](https://onco.cc/cancers/sarcoma/)
- technologies: [CRISPR functional genomics](https://onco.cc/technologies/crispr-screens/), [Patient-derived xenografts](https://onco.cc/technologies/pdx-models/), [PROTACs & molecular glues (targeted protein degradation)](https://onco.cc/technologies/protac-degrader/)
- companies: [C4 Therapeutics](https://onco.cc/companies/c4-therapeutics/)
- terms: [Gene fusion](https://onco.cc/terms/gene-fusion/)
- bottlenecks: [Rare and paediatric cancers without markets](https://onco.cc/bottlenecks/b-rare-cancers/), [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)
- key papers: [Drugging the 'undruggable' cancer targets](https://onco.cc/key-papers/paper-dang-nat-rev-cancer/)
- roadmaps: [Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome](https://onco.cc/roadmaps/epigenetics-roadmap/), [Paediatric oncology roadmap: cooperative-group cures → engineered immunity → drugs developed for children first](https://onco.cc/roadmaps/paediatric-oncology-roadmap/)

---
JSON: https://onco.cc/api/v1/entities/idea-bio1-fusion-tf-degraders.json