Reviews:
The second European interdisciplinary Ewing sarcoma research summit – A joint effort to deconstructing the multiple layers of a complex disease
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Abstract
Heinrich Kovar1,2,*, James Amatruda3,*, Erika Brunet4,*, Stefan Burdach5,*, Florencia Cidre-Aranaz6,*, Enrique de Alava7,*, Uta Dirksen8,*, Wietske van der Ent9,10,*, Patrick Grohar11,*, Thomas G. P. Grünewald12,*, Lee Helman13,*, Peter Houghton14,*, Kristiina Iljin15,*, Eberhard Korsching16,*, Marc Ladanyi17,*, Elizabeth Lawlor18,*, Stephen Lessnick19,*, Joseph Ludwig20,*, Paul Meltzer21,*, Markus Metzler22,*, Jaume Mora23,*, Richard Moriggl24,25,*, Takuro Nakamura26,*, Theodore Papamarkou27,*, Branka Radic Sarikas28,*, Francoise Rédini29,*, Guenther H. S. Richter5,*, Claudia Rossig8,*, Keri Schadler30,*, Beat W. Schäfer31,*, Katia Scotlandi32,*, Nathan C. Sheffield28,*, Anang Shelat33,*, Ewa Snaar-Jagalska10,*, Poul Sorensen34,*, Kimberly Stegmaier35,*, Elizabeth Stewart36,*, Alejandro Sweet-Cordero37,*, Karoly Szuhai38,*, Oscar M. Tirado39,*, Franck Tirode9,*, Jeffrey Toretsky40,*, Kalliopi Tsafou40,*, Aykut Üren40,*, Andrei Zinovyev9,41,42,* and Olivier Delattre9,*
1 Children’s Cancer Research Institute, St. Anna Kinderkrebsforschung, Vienna, Austria
2 Department of Pediatrics, Medical University Vienna, Vienna, Austria
3 Departments of Pediatrics, Molecular Biology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
4 Museum National d’Histoire Naturelle, INSERM U1154, CNRS 7196, Paris, France
5 Children’s Cancer Research Center and Department of Pediatrics, Klinikum rechts der Isar, Technical University and Comprehensive Cancer Center Munich (CCCM), Munich, Germany
6 Unidad de Tumores Sólidos Infantiles, Área de Genética Humana, Instituto de Investigación de Enfermedades Raras, Instituto de Salud Carlos III, Madrid, Spain
7 Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital /CSIC/University de Sevilla, Department of Pathology, Seville, Spain
8 University Children´s Hospital Muenster, Pediatric Hematology and Oncology, Muenster, Germany
9 INSERM U830, Laboratoire de Génétique et Biologie des Cancers, Institut Curie, Paris, France
10 Institute of Biology, Leiden University, Leiden, The Netherlands
11 Van Andel Institute, Center for Cancer and Cell Biology and Helen DeVos Children’s Hospital, Grand Rapids, MI, USA
12 Laboratory for Pediatric Sarcoma Biology, Institute of Pathology of the LMU Munich, Munich, Germany
13 Center for Cancer Rearch, NCI, NIH, Bethesda, MA, USA
14 Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, USA
15 VTT Technical Research Centre of Finland Ltd, Espoo, Finland
16 Institute of Bioinformatics, Faculty of Medicine, University of Muenster, Muenster, Germany
17 Department of Pathology and Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
18 Department of Pediatrics and Department of Pathology, University of Michigan, Ann Arbor, MI, USA
19 Center for Childhood Cancer and Blood Disorders, Nationwide Children’s Hospital, and the Division of Pediatric Hematology/Oncology/BMT, The Ohio State University, Columbus, OH, USA
20 Department of Sarcoma Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
21 Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
22 Pediatric Oncology and Hematology, University Hospital Erlangen, Erlangen, Germany
23 Department of Pediatric Oncology, Sant Joan de Déu Hospital, Barcelona, Spain
24 Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria
25 Institute of Animal Breeding and Genetics, University of Veterinary Medicine and Medical University, Vienna, Austria
26 Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan
27 University of Glasgow, School of Mathematics and Statistics, Glasgow, UK
28 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
29 INSERM UMR957, Université de Nantes, Nantes, France
30 Department of Pediatrics Research, MD Anderson Cancer Center, Houston, TX, USA
31 Department of Oncology and Children’s Research Center, University Children‘s Hospital, Zurich, Switzerland
32 CRS Development of Biomolecular Therapies, Experimental Oncology Lab, Rizzoli Institute, Bologna, Italy
33 Department of Chemical Biology and Therapeutics, St. Jude Children’s Research Hospital, Memphis,TN, USA
34 Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada
35 Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children’s Hospital, Boston, MA, USA
36 Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA
37 Division of Hematology and Oncology, Department of Pediatrics, Stanford University, Stanford, CA, USA
38 Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands
39 Sarcoma Research Group, Molecular Oncology Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain
40 Department of Oncology, Georgetown University School of Medicine, Washington, DC, USA
41 INSERM, U900, Paris, France
42 Ecole des Mines ParisTech, Fontainbleau, France
* These authors have contributed equally to this work
Correspondence to:
Heinrich Kovar, email:
Keywords: Ewing sarcoma, epigenetics, development, therapy, microenvironment
Received: October 20, 2015 Accepted: January 14, 2016 Published: January 18, 2016
Abstract
Despite multimodal treatment, long term outcome for patients with Ewing sarcoma is still poor. The second “European interdisciplinary Ewing sarcoma research summit” assembled a large group of scientific experts in the field to discuss their latest unpublished findings on the way to the identification of novel therapeutic targets and strategies. Ewing sarcoma is characterized by a quiet genome with presence of an EWSR1-ETS gene rearrangement as the only and defining genetic aberration. RNA-sequencing of recently described Ewing-like sarcomas with variant translocations identified them as biologically distinct diseases. Various presentations adressed mechanisms of EWS-ETS fusion protein activities with a focus on EWS-FLI1. Data were presented shedding light on the molecular underpinnings of genetic permissiveness to this disease uncovering interaction of EWS-FLI1 with recently discovered susceptibility loci. Epigenetic context as a consequence of the interaction between the oncoprotein, cell type, developmental stage, and tissue microenvironment emerged as dominant theme in the discussion of the molecular pathogenesis and inter- and intra-tumor heterogeneity of Ewing sarcoma, and the difficulty to generate animal models faithfully recapitulating the human disease. The problem of preclinical development of biologically targeted therapeutics was discussed and promising perspectives were offered from the study of novel in vitro models. Finally, it was concluded that in order to facilitate rapid pre-clinical and clinical development of novel therapies in Ewing sarcoma, the community needs a platform to maintain knowledge of unpublished results, systems and models used in drug testing and to continue the open dialogue initiated at the first two Ewing sarcoma summits.
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