2. Academic Validation
  3. Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology

Functional genomic analysis of epithelioid sarcoma reveals distinct proximal and distal subtype biology

  • Clin Transl Med. 2022 Jul;12(7):e961. doi: 10.1002/ctm2.961.
Samuel V Rasmussen 1,  Jia Xiang Jin 2,  Lissett R Bickford 1,  Andrew D Woods 1,  Felix Sahm 3 4 5,  Kenneth A Crawford 1,  Kiyo Nagamori 1,  Hiroaki Goto 6,  Keila E Torres 7,  Angelo Sidoni 8,  Erin R Rudzinski 9,  Khin Thway 10 11,  Robin L Jones 10 12,  Alessio Ciulli 13,  Hollis Wright 14,  Melvin Lathara 14,  Ganapati Srinivasa 14,  Kavya Kannan 14,  Paul H Huang 10 11,  Thomas G P Grünewald 2 3,  Noah E Berlow 1,  Charles Keller 1
Affiliations

Affiliations

  • 1 Children's Cancer Therapy Development Institute, Beaverton, Oregon, USA.
  • 2 Division of Translational Pediatric Sarcoma Research, Hopp Children's Cancer Center (KiTZ), German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
  • 3 Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
  • 4 Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • 5 Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
  • 6 Division of Hematology/Oncology, Kanagawa Children's Medical Center, Yokohama, Japan.
  • 7 Sarcoma Surgical Oncology, MD Anderson Cancer Center, Houston, Texas, USA.
  • 8 Section of Pathology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • 9 Department of Pathology, Seattle Children's Hospital, Seattle, Washington, USA.
  • 10 Sarcoma Unit, Royal Marsden Hospital, Belmont, UK.
  • 11 Division of Molecular Pathology, Institute of Cancer Research, London, UK.
  • 12 Division of Clinical Studies, Institute of Cancer Research, London, UK.
  • 13 School of Life Sciences, University of Dundee, Dundee, UK.
  • 14 Omics Data Automation, Beaverton, Oregon, USA.
PMID: 35839307 DOI: 10.1002/ctm2.961
Abstract

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.

Keywords

SMARCB1; distal; epithelioid sarcoma; functional genomics; proximal.

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