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Updated: Oct 11, 2025
Development and Maintenance of a Preclinical Patient Derived Tumor Xenograft Model for the Investigation of Novel Anti-Cancer Therapies
Published on: September 30, 2016
Novel patient-derived models of desmoplastic small round cell tumor confirm a targetable dependency on ERBB signaling
Roger S Smith1, Igor Odintsov1,2, Zebing Liu1,2
1Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
Abstract:
Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) translocation, which fuses the transcriptional regulatory domain of EWSR1 with the DNA-binding domain of WT1, resulting in the oncogenic EWSR1-WT1 fusion protein. The paucity of DSRCT disease models has hampered preclinical therapeutic studies on this aggressive cancer. Here, we developed preclinical disease models and mined DSRCT expression profiles to identify genetic vulnerabilities that could be leveraged for new therapies. We describe four DSRCT cell lines and one patient-derived xenograft model. Transcriptomic, proteomic and biochemical profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Antagonizing EGFR function with shRNAs, small-molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited proliferation of DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for evaluating EGFR antagonists in patients with DSRCT. This article has an associated First Person interview with the joint first authors of the paper.
Insights
New preclinical models for desmoplastic small round cell tumor (DSRCT) reveal ERBB pathway activation. Targeting the epidermal growth factor receptor (EGFR) pathway with inhibitors significantly reduced DSRCT tumor growth in preclinical studies.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Desmoplastic small round cell tumor (DSRCT) is an aggressive cancer driven by the EWSR1-WT1 fusion protein.
- Limited availability of DSRCT disease models has hindered the development of effective therapies.
Purpose of the Study:
- To develop preclinical models for DSRCT.
- To identify genetic vulnerabilities and therapeutic targets in DSRCT by analyzing expression profiles.
Main Methods:
- Established four DSRCT cell lines and one patient-derived xenograft model.
- Performed transcriptomic, proteomic, and biochemical profiling.
- Investigated the role of the ERBB pathway and EGFR signaling in DSRCT proliferation.
- Tested the efficacy of EGFR antagonists (shRNAs, small-molecule inhibitors, antibodies) in vitro and in vivo.
Main Results:
- DSRCT models exhibited activation of the ERBB pathway, with EWSR1-WT1 upregulating ERBB ligands.
- EGFR, ERBB2, ERK1/2, and AKT were activated by ERBB ligands, promoting cell growth.
- Inhibition of EGFR signaling suppressed DSRCT cell proliferation.
- Combination therapy with cetuximab and afatinib significantly inhibited tumor growth in DSRCT xenografts.
Conclusions:
- The ERBB pathway, particularly EGFR signaling, is a critical vulnerability in DSRCT.
- EGFR antagonists show significant therapeutic potential for DSRCT.
- Clinical evaluation of EGFR antagonists in DSRCT patients is warranted.
