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Mini-Review on Targeted Treatment of Desmoplastic Small Round Cell Tumor
Tomas S Bexelius1,2, Ajla Wasti3,4, Julia C Chisholm1,5
1Children and Young People's Unit, Royal Marsden Hospital NHS Foundation Trust, Sutton, United Kingdom.
Abstract:
Desmoplastic small round cell tumor (DSRCT) is a devastating disease which most commonly affects adolescents, with a male predominance. Despite the best multimodality treatment efforts, most patients will ultimately not survive more than 3-5 years after diagnosis. Some research trials in soft-tissue sarcoma and Ewing sarcoma include DSRCT patients but few studies have been tailored to the specific clinical needs and underlying cytogenetic abnormalities characterizing this disease such as the typical EWSR1-WT1 gene fusion. Downstream activation of EWSR1-WT1 gene fusion includes signaling pathways of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and insulin growth factor (IGF)-1. Other biological pathways that are activated and expressed in DSRCT cells include endothelial growth factor receptor (EGFR), androgen receptor pathway, c-KIT, MET, and transforming growth factor (TGF) beta. Investigation of somatic mutations, copy number alterations (CNA), and chromosomes in DSRCT samples suggests that deregulation of mesenchymal-epithelial reverse transition (MErT)/epithelial-mesenchymal transition (EMT) and DNA damage repair (DDR) may be important in DSRCT. This mini review looks at known druggable targets in DSRCT and existing clinical evidence for targeted treatments, particularly multityrosine kinase inhibitors such as pazopanib, imatinib, and sorafenib alone or in combination with other agents such as mTOR (mammalian target of rapamycin) inhibitors. The aim is to increase shared knowledge about current available treatments and identify gaps in research to further efforts toward clinical development of targeted agents.
Insights
Desmoplastic small round cell tumor (DSRCT) is a rare cancer. This review explores targeted therapies and druggable targets, like tyrosine kinase inhibitors, to improve outcomes for DSRCT patients.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Desmoplastic small round cell tumor (DSRCT) is an aggressive cancer primarily affecting adolescents, with a poor prognosis despite multimodality treatments.
- Existing research often groups DSRCT with other sarcomas, lacking focus on its unique genetic drivers, such as the EWSR1-WT1 gene fusion.
- Key signaling pathways implicated in DSRCT include PDGF, VEGF, IGF-1, EGFR, androgen receptor, c-KIT, MET, and TGF-beta.
Purpose of the Study:
- To review known druggable targets in DSRCT.
- To summarize existing clinical evidence for targeted treatments in DSRCT.
- To identify research gaps and guide future clinical development of targeted agents.
Main Methods:
- Literature review of DSRCT research focusing on genetic abnormalities and targeted therapies.
- Analysis of downstream signaling pathways activated by the EWSR1-WT1 gene fusion.
- Investigation of somatic mutations, copy number alterations, and chromosomal abnormalities in DSRCT samples.
Main Results:
- Druggable targets identified include pathways regulated by PDGF, VEGF, IGF-1, EGFR, androgen receptor, c-KIT, MET, and TGF-beta.
- Deregulation of mesenchymal-epithelial reverse transition (MErT)/epithelial-mesenchymal transition (EMT) and DNA damage repair (DDR) pathways are implicated in DSRCT.
- Multityrosine kinase inhibitors (e.g., pazopanib, imatinib, sorafenib) and mTOR inhibitors are key targeted agents under investigation.
Conclusions:
- Targeted therapies, particularly multityrosine kinase inhibitors, show promise for DSRCT treatment.
- Further research is needed to optimize the use of these agents and address specific DSRCT vulnerabilities.
- Understanding DSRCT's molecular landscape is crucial for developing more effective, personalized treatment strategies.
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