Rewiring the Fusion Oncoprotein EWSR1::FLI1 in Ewing Sarcoma with Bivalent Small Molecules

Area of Science:

• Molecular Biology
• Cancer Research
• Drug Discovery

Background:

• Dysregulated transcription is a key feature of cancer.
• Chemically induced proximity (CIP) strategies use bivalent small molecules to control gene expression.
• Fusion transcription factors drive many pediatric cancers, presenting therapeutic challenges.

Purpose of the Study:

• To investigate the potential of bivalent small molecules to relocalize DNA-bound transcriptional machinery.
• To target fusion transcription factors, such as EWSR1::FLI1, implicated in pediatric malignancies.
• To develop a novel molecule for inducing targeted gene expression in cancer.

Main Methods:

• Development of a bivalent small molecule, EB-TCIP.
• Recruitment of FKBP12^F36V-tagged EWSR1::FLI1 to BCL6-bound DNA sites.
• Assessment of chromatin remodeling and gene expression changes.

Main Results:

• EB-TCIP successfully recruited EWSR1::FLI1 to BCL6-bound DNA.
• This recruitment led to rapid chromatin remodeling.
• Expression of BCL6 target genes was induced, demonstrating proof-of-concept.

Conclusions:

• DNA-binding proteins with pioneering activity, like EWSR1::FLI1, can be therapeutically relocalized on chromatin.
• This strategy can induce the expression of previously repressed genes.
• Findings guide the development of future bivalent molecules for cancer therapy.