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Updated: Jun 23, 2025
A Mouse Model of Incompletely Resected Soft Tissue Sarcoma for Testing Neoadjuvant Therapies
Published on: July 28, 2020
Modeling Extraordinary Response Through Targeting Secondary Alterations in Fusion-Associated Sarcoma
Fabio Vanoli1, Evan Song1, Josephine K Dermawan2
1Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Purpose:
Targeted therapy in translocation-associated sarcomas has been limited to oncogenic activation of tyrosine kinases or ligands while gene fusions resulting in aberrant expression of transcription factors have been notoriously difficult to target. Moreover, secondary genetic alterations in sarcomas driven by translocations are uncommon, comprising mostly alterations in tumor suppressor genes (TP53, CDKN2A/B). Our study was triggered by an index patient showing a dramatic clinical response by targeting the secondary BRAF V600E mutation in a metastatic angiomatoid fibrous histiocytoma (AFH) harboring the typical EWSR1::CREB1 fusion.
Materials And Methods:
The patient, a 28-year-old female, was diagnosed with an AFH of the thigh and followed a highly aggressive clinical course, with rapid multifocal local recurrence within a year and widespread distant metastases (adrenal, bone, liver, lung). The tumor showed characteristic morphologic features, with histiocytoid cells intermixed with hemorrhagic cystic spaces and lymphoid aggregates. In addition to the pathognomonic EWSR1::CREB1 fusion, targeted DNA sequencing revealed in both primary and adrenal metastatic sites a hot spot BRAF V600E mutation and a CDKN2A/B deletion. Accordingly, the patient was treated with a BRAF-MEK inhibitor combination (encorafenib/binimetinib) showing an excellent but short-lived response.
Results:
Using a CRISPR-Cas9 approach, we introduced the BRAF c.1799 T>A point mutation in human embryonic stem (hES) cells harboring a conditional EWSR1 (exon7)::CREB1 (exon7) translocation and further differentiated to mesenchymal progenitors (hES-MP) before fusion expression. The cells maintained the fusion transcript expression and the AFH core gene signature while responding to treatment with encorafenib and binimetinib.
Conclusion:
These results highlight that additional targeted DNA NGS in chemotherapy-resistant translocation-associated sarcomas may reveal actionable oncogenic drivers occurring as secondary genetic events during disease progression.
Insights
Targeting secondary BRAF V600E mutations in translocation-associated sarcomas, like angiomatoid fibrous histiocytoma, can be effective. This study demonstrates the potential of identifying and targeting these secondary genetic events for improved treatment outcomes.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Targeted therapy for translocation-associated sarcomas is often limited, especially for gene fusions involving transcription factors.
- Secondary genetic alterations in these sarcomas are infrequent, typically involving tumor suppressor genes like TP53 and CDKN2A/B.
Purpose of the Study:
- To investigate the potential of targeting secondary genetic mutations in translocation-associated sarcomas.
- Triggered by a patient with metastatic angiomatoid fibrous histiocytoma (AFH) and an EWSR1::CREB1 fusion who responded to BRAF V600E mutation-targeted therapy.
Main Methods:
- A patient with aggressive AFH was treated with a BRAF-MEK inhibitor combination (encorafenib/binimetinib) after identification of EWSR1::CREB1 fusion, BRAF V600E mutation, and CDKN2A/B deletion.
- CRISPR-Cas9 was used to introduce the BRAF V600E mutation into human embryonic stem cell-derived mesenchymal progenitors with the EWSR1::CREB1 translocation.
Main Results:
- The patient exhibited a dramatic, albeit short-lived, clinical response to BRAF-MEK inhibition.
- Engineered cells with the EWSR1::CREB1 fusion and BRAF V600E mutation maintained fusion expression and responded to encorafenib/binimetinib treatment.
Conclusions:
- Targeted next-generation sequencing (NGS) in chemotherapy-resistant sarcomas may uncover actionable secondary oncogenic drivers.
- Identifying and targeting these secondary events offers a potential therapeutic strategy for translocation-associated sarcomas.
