The second European interdisciplinary Ewing sarcoma research summit - A joint effort to deconstructing the multiple layers of a complex disease

// Heinrich Kovar 1,2,* , James Amatruda 3,* , Erika Brunet 4,* , Stefan Burdach 5,* , Florencia Cidre-Aranaz 6,* , Enrique de Alava 7,* , Uta Dirksen 8,* , Wietske van der Ent 9,10,* , Patrick Grohar 11,* , Thomas G. P. Grünewald 12,* , Lee Helman 13,* , Peter Houghton 14,* , Kristiina Iljin 15,* , Eberhard Korsching 16,* , Marc Ladanyi 17,* , Elizabeth Lawlor 18,* , Stephen Lessnick 19,* , Joseph Ludwig 20,* , Paul Meltzer 21,* , Markus Metzler 22,* , Jaume Mora 23,* , Richard Moriggl 24,25,* , Takuro Nakamura 26,* , Theodore Papamarkou 27,* , Branka Radic Sarikas 28,* , Francoise Rédini 29,* , Guenther H. S. Richter 5,* , Claudia Rossig 8,* , Keri Schadler 30,* , Beat W. Schäfer 31,* , Katia Scotlandi 32,* , Nathan C. Sheffield 28,* , Anang Shelat 33,* , Ewa Snaar-Jagalska 10,* , Poul Sorensen 34,* , Kimberly Stegmaier 35,* , Elizabeth Stewart 36,* , Alejandro Sweet-Cordero 37,* , Karoly Szuhai 38,* , Oscar M. Tirado 39,* , Franck Tirode 9,* , Jeffrey Toretsky 40,* , Kalliopi Tsafou 40,* , Aykut Üren 40,* , Andrei Zinovyev 9,41,42,* and Olivier Delattre 9,* 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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