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Updated: May 25, 2026
Mapping the Structure-Function Relationships of Disordered Oncogenic Transcription Factors Using Transcriptomic Analysis
Published on: June 27, 2020
Small-molecule screen identifies modulators of EWS/FLI1 target gene expression and cell survival in Ewing's sarcoma
Aleksandar Boro1, Kathya Prêtre, Florian Rechfeld
1Department of Oncology and Children's Research Center, University Children's Hospital, Steinwiesstrasse 75, Zurich, Switzerland.
Abstract:
Ewing's sarcoma family of tumors (EFT) is characterized by the presence of chromosomal translocations leading to the expression of oncogenic transcription factors such as, in the majority of cases, EWS/FLI1. Because of its key role in Ewing's sarcoma development and maintenance, EWS/FLI1 represents an attractive therapeutic target. Here, we characterize PHLDA1 as a novel direct target gene whose expression is repressed by EWS/FLI1. Using this gene and additional specific well-characterized target genes such as NROB1, NKX2.2 and CAV1, all activated by EWS/FLI1, as a read-out system, we screened a small-molecule compound library enriched for FDA-approved drugs that modulated the expression of EWS/FLI1 target genes. Among a hit-list of nine well-known drugs such as camptothecin, fenretinide, etoposide and doxorubicin, we also identified the kinase inhibitor midostaurin (PKC412). Subsequent experiments demonstrated that midostaurin is able to induce apoptosis in a panel of six Ewing's sarcoma cell lines in vitro and can significantly suppress xenograft tumor growth in vivo. These results suggest that midostaurin might be a novel drug that is active against Ewing's cells, which might act by modulating the expression of EWS/FLI1 target genes.
Insights
Midostaurin, a kinase inhibitor, shows promise in treating Ewing's sarcoma family of tumors (EFT). It effectively targets EWS/FLI1, a key factor in EFT development, by modulating its gene expression and inducing cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ewing's sarcoma family of tumors (EFT) is driven by oncogenic transcription factors, primarily EWS/FLI1, resulting from chromosomal translocations.
- EWS/FLI1 plays a crucial role in the development and maintenance of EFT, making it a significant therapeutic target.
Purpose of the Study:
- To identify novel therapeutic agents targeting EWS/FLI1 activity in EFT.
- To characterize PHLDA1 as a new direct target gene repressed by EWS/FLI1 and use it as a readout for drug screening.
Main Methods:
- Screened a library of FDA-approved drugs for compounds that modulate EWS/FLI1 target gene expression.
- Utilized PHLDA1, NROB1, NKX2.2, and CAV1 as readouts for EWS/FLI1 activity.
- Evaluated the efficacy of identified compounds, including midostaurin, in Ewing's sarcoma cell lines in vitro and in xenograft models in vivo.
Main Results:
- Identified nine known drugs, including camptothecin, fenretinide, etoposide, and doxorubicin, that modulate EWS/FLI1 target genes.
- Discovered midostaurin (PKC412), a kinase inhibitor, as a potent modulator of EWS/FLI1 target gene expression.
- Demonstrated that midostaurin induces apoptosis in six Ewing's sarcoma cell lines and suppresses tumor growth in vivo.
Conclusions:
- Midostaurin is a potential novel therapeutic agent for Ewing's sarcoma.
- Midostaurin's anti-cancer activity may stem from its ability to modulate EWS/FLI1 target gene expression.
