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EWSR1-WT1 Target Genes and Therapeutic Options Identified in a Novel DSRCT In Vitro Model
Margit Bleijs1,2, Corine Pleijte1,2, Sem Engels1,2
1Princess Máxima Center for Pediatric Oncology, 3584 CT Utrecht, The Netherlands.
Abstract:
Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive soft tissue sarcoma with a lack of effective treatment options and a poor prognosis. DSRCT is characterized by a chromosomal translocation, resulting in the EWSR1-WT1 gene fusion. The molecular mechanisms driving DSRCT are poorly understood, and a paucity of preclinical models hampers DSRCT research. Here, we establish a novel primary patient-derived DSRCT in vitro model, recapitulating the original tumor. We find that EWSR1-WT1 expression affects cell shape and cell survival, and we identify downstream target genes of the EWSR1-WT1 fusion. Additionally, this preclinical in vitro model allows for medium-throughput drug screening. We discover sensitivity to several drugs, including compounds targeting RTKs. MERTK, which has been described as a therapeutic target for several malignancies, correlates with EWSR1-WT1 expression. Inhibition of MERTK with the small-molecule inhibitor UNC2025 results in reduced proliferation of DSRCT cells in vitro, suggesting MERTK as a therapeutic target in DSRCT. This study underscores the usefulness of preclinical in vitro models for studying molecular mechanisms and potential therapeutic options.
Insights
A new in vitro model for Desmoplastic small round cell tumor (DSRCT) was developed. This model identified MERTK as a potential therapeutic target, showing promise for treating this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive soft tissue sarcoma with limited treatment options.
- The underlying molecular mechanisms of DSRCT are not well understood, hindering research and therapeutic development.
- A lack of effective preclinical models has significantly hampered progress in DSRCT research.
Purpose of the Study:
- To establish a novel patient-derived in vitro model for DSRCT.
- To investigate the molecular mechanisms driven by the EWSR1-WT1 gene fusion in DSRCT.
- To identify potential therapeutic targets and screen for effective drug treatments for DSRCT.
Main Methods:
- Development of a primary patient-derived DSRCT in vitro model.
- Analysis of EWSR1-WT1 gene fusion expression and its downstream effects on cell behavior.
- Medium-throughput drug screening and evaluation of MERTK inhibition using UNC2025.
Main Results:
- The established in vitro model accurately recapitulates the original DSRCT tumor characteristics.
- EWSR1-WT1 expression influences cell shape and survival, with identified downstream target genes.
- Drug screening revealed sensitivity to RTK inhibitors, with MERTK identified as a potential therapeutic target, showing efficacy upon inhibition.
Conclusions:
- The novel DSRCT in vitro model is valuable for studying molecular mechanisms and facilitating drug discovery.
- MERTK is a promising therapeutic target for DSRCT, warranting further investigation.
- Targeting MERTK may offer a new treatment strategy for patients with Desmoplastic small round cell tumor.
