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Published on: July 25, 2020
Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology
Samuel V Rasmussen1, Jia Xiang Jin2, Lissett R Bickford1
1Children's Cancer Therapy Development Institute, Beaverton, Oregon, USA.
Background:
Metastatic epithelioid sarcoma (EPS) remains a largely unmet clinical need in children, adolescents and young adults despite the advent of EZH2 inhibitor tazemetostat.
Methods:
In order to realise consistently effective drug therapies, a functional genomics approach was used to identify key signalling pathway vulnerabilities in a spectrum of EPS patient samples. EPS biopsies/surgical resections and cell lines were studied by next-generation DNA exome and RNA deep sequencing, then EPS cell cultures were tested against a panel of chemical probes to discover signalling pathway targets with the most significant contributions to EPS tumour cell maintenance.
Results:
Other biologically inspired functional interrogations of EPS cultures using gene knockdown or chemical probes demonstrated only limited to modest efficacy in vitro. However, our molecular studies uncovered distinguishing features (including retained dysfunctional SMARCB1 expression and elevated GLI3, FYN and CXCL12 expression) of distal, paediatric/young adult-associated EPS versus proximal, adult-associated EPS.
Conclusions:
Overall results highlight the complexity of the disease and a limited chemical space for therapeutic advancement. However, subtle differences between the two EPS subtypes highlight the biological disparities between younger and older EPS patients and emphasise the need to approach the two subtypes as molecularly and clinically distinct diseases.
Insights
Metastatic epithelioid sarcoma (EPS) in young patients is complex. Functional genomics identified distinct molecular features in pediatric EPS, suggesting tailored therapies are needed for these distinct subtypes.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Metastatic epithelioid sarcoma (EPS) presents a significant clinical challenge, particularly in pediatric, adolescent, and young adult populations.
- Current treatments, including EZH2 inhibitors like tazemetostat, offer limited efficacy for these age groups.
Purpose of the Study:
- To identify key signaling pathway vulnerabilities in epithelioid sarcoma using a functional genomics approach.
- To discover novel therapeutic targets for EPS by analyzing patient samples and cell lines.
Main Methods:
- Employed next-generation DNA exome and RNA deep sequencing on EPS patient biopsies and cell lines.
- Utilized functional genomics, including gene knockdown and chemical probes, to assess signaling pathway targets.
- Investigated molecular differences between pediatric/young adult-associated EPS and adult-associated EPS.
Main Results:
- Functional genomics studies revealed limited efficacy of current therapeutic strategies in vitro.
- Identified distinct molecular features differentiating pediatric/young adult EPS from adult EPS, including SMARCB1, GLI3, FYN, and CXCL12 expression levels.
- Highlighted retained dysfunctional SMARCB1 expression in pediatric EPS.
Conclusions:
- Epithelioid sarcoma is a complex disease with limited therapeutic options.
- Distinct molecular and clinical characteristics exist between pediatric/young adult and adult EPS subtypes.
- Future therapeutic strategies should consider these subtypes as distinct diseases.
