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Forschungsbericht Science Report FORSCHUNGSBERICHT SCIENCE REPORT2017/2018 ST. ANNA KINDERKREBSFORSCHUNG ST. ANNA CHILDREN’S CANCER RESEARCH INSTITUTE TUMOR BIOLOGY Understanding tumor heterogeneity and relapse in neuroblastoma patients to allow adequate treatment options. MOLECULAR MICROBIOLOGY LCH BIOLOGY Clinically important Targeted resistant mutations in Philadelphia inhibition chromosome-positive leukemias. of the MAPK pathway leads to a STUDIES & STATISTICS rapid and sustained clinical response in severe multisystem LCH. Busulfan and melphalan is considered standard high-dose chemotherapy for high-risk neuroblastoma. GENETICS OF LEUKEMIAS A novel genetic MOLECULAR BIOLOGY OF SOLID TUMORS subtype of leukemia. Understanding mechanisms EPIGENOME-BASED PRECISION MEDICINE of tumor cell plasticity EPIGENETIC and its role in diversity in Ewing sarcoma metastasis. Ewing sarcoma. MORE SCIENCE REPORTS INSIDE >>> [ 06 ] Forschungsbericht St. Anna Kinderkrebsforschung | Science Report St. Anna Children’s Cancer Research Institute Inhalt Einleitung Vorwort des Institutsleiters 10 Vorwort des wissenschaftlichen Direktors 12 30 Jahre – unseren Spendern sei Dank! 14 Daten & Fakten Kompetitive Drittmittel 2018 20 Zuweisung der Geldmittel 2018 20 Finanzierung 2018 20 Nationen 21 Personelle Zusammensetzung 21 PatientInnenaufkommen im S2IRP 22 2-Jahres-Überlebensrate krebskranker Kinder 23 5-Jahres-Überlebensrate krebskranker Kinder 24 Forschungsnetzwerke 26 Inhalt Forschungsbericht I St. Anna Kinderkrebsforschung | Science Report St. Anna Cancer Research Institute [ 07 ] Science Reports ■ Clinically important resistant mutations in Philadelphia Introduction 30 ■ chromosome-positive leukemias 84 Science Reports 2017 ■ Allogeneic Stem Cell Transplantation for ■ Targeted inhibition of the MAPK pathway children with Acute Lymphoblastic Leukemia: leads to a rapid and sustained clinical response Outcome after mismatched-donor in severe multisystem LCH 38 transplantation is influenced by Disease Risk 90 ■ Understanding mechanisms of tumor cell plasticity and its role in Career Ewing sarcoma metastasis 42 Working at CCRI 98 ■ Busulfan and melphalan is considered standard high-dose chemotherapy for If you want to apply for a position 99 high-risk neuroblastoma. 46 Scientific Staff 100 ■ A novel fusion gene in treatment-resistant pediatric myeloid neoplasia 50 Finanzbericht ■ A novel genetic subtype of leukemia 56 Richtlinien zur Spendenverwendung 104 ■ Epigenetic diversity in Ewing sarcoma 60 Mittelherkunft 106 Science Reports 2018 Mittelverwendung 107 ■ Understanding tumor heterogeneity and relapse in neuroblastoma patients to Anhang allow adequate treatment options 64 International Grants 110 ■ Investigating bone marrow dissemination in metastatic neuroblastoma 68 National Grants 112 ■ Establishing diagnoses in children with rare Acknowledgments 114 hematological cytopenias via modern genomic Bachelor-, Master/Diploma- and PhD-Theses 116 approaches 72 Publications 2017 118 ■ No evidence that addition of subcutaneous IL-2 to immunotherapy with dinutuximab Publications 2018 126 beta, given as an 8 h infusion, improved Impressum 136 outcomes in patients with high-risk neuroblastoma, hence, dinutuximab beta Fundraising 137 alone should thus be considered the standard of care 76 ■ Path to overcoming the threat of adenovirus infections in pediatric stem cell transplant recipients 78 Inhalt Einleitung [ 10 ] Forschungsbericht St. Anna Kinderkrebsforschung | Science Report St. Anna Children’s Cancer Research Institute Vorwort des Institutsleiters Zulassung einer Immuntherapie beim Hochrisiko- Neuroblastom, die von der St. Anna Kinderkrebsfor- schung über viele Jahre maßgeblich mitentwickelt wurde. Darüber hinaus sind uns viele weitere wichtige Publikationen und wissenschaftliche Meilensteine gelungen, wie Sie im vorliegenden ann man auf wissenschaftliche Erfolge Zweijahresbericht im Detail sehen. stolz sein? Ja, umso mehr, wenn sie dazu beitragen, junges Leben zu retten. Als weiteres Highlight ist zu erwähnen, dass der Fortschritte in der Grundlagenwissen- St. Anna Kinderkrebsforschung 2017 gemeinsam schaft, der klinischen Wissenschaft mit dem St. Anna Kinderspital von der und der Diagnostik bringen uns dabei voran, das Europäischen Union als einer von nur zwei österrei- Ksehen wir als unsere Aufgabe und Pflicht und als chischen Institutionen die Auszeichnung Expertise- unser Ziel. zentrum verliehen und sie zur Koordinatorin eines Ich glaube, in unserem Fall sind sowohl Stolz als europäischen Referenznetzwerks gegen Kinderkrebs auch Freude und Dankbarkeit zulässig. Denn im (ERN PaedCan) ernannt wurde. Die Auszeichnung Jahr nach dem 30. Jubiläum der St. Anna Kinder- ist auch die Basis für viele assoziierte Folgeprojekte, krebsforschung dürfen wir mit diesem Jahresbericht die im Jahr 2018 anliefen und alle zum Ziel haben, auch auf die Erfolge zurückblicken, die in den die Kräfte gegen Kinderkrebs zu bündeln und zu letzten beiden Jahren von unserem Institut erbracht optimieren. wurden. Entsprechend konnten wir uns auch wieder über 2017 veröffentlichte eine unserer jungen Fördergelder freuen. Die Zuwendungen der Forscherinnen gemeinsam mit ihren wissenschaftli- Europäischen Union und nationale Forschungsför- chen Partnern eine wichtige und weithin beachtete derungen machten 2018 in puncto Förderungen Publikation in der renommierten Fachzeitschrift zum erfolgreichsten Jahr in der Geschichte der St. „Nature Medicine“, und zwar zum Thema Epigenetik Anna Kinderkrebsforschung und stärken unseren beim Ewing-Sarkom. Im gleichen Jahr erfolgte die Ehrgeiz, auch in Zukunft ganz vorne in der Liga der Einleitung Forschungsbericht St. Anna Kinderkrebsforschung | Science Report St. Anna Children’s Cancer Research Institute [ 11 ] Univ.-Prof. Dr. Wolfgang Holter internationalen Spitzenforschung zum Wohle krebskranker Kinder mitzumischen. Unser Institut wurde vor über 30 Jahren begründet, da liegt ein Generationenwechsel in der Natur der Sache. Gründungsmitglieder gingen in den wohlverdienten Ruhestand, junge, aufstrebende krebskranker Kinder vertraut sind. Es ist eine große Forscherinnen und Forscher bereicherten unser Freude, einen so wertvollen Zugewinn zu unserem Institut. So danken wir besonders Herrn Doz. Dr. wissenschaftlichen Team verzeichnen zu können. Gerhard Fritsch (Gruppe „Klinische Zellbiologie“) und Herrn Univ.-Doz. Dr. Peter Ambros und Frau Mit dem vorliegenden wissenschaftlichen Dr. Inge Ambros (Gruppe „Tumorbiologie“) für Jahresbericht möchte ich mich, auch im Namen aller ihren langjährigen Einsatz rund um das Forschungs- Mitarbeiterinnen und Mitarbeiter, sehr herzlich bei institut. Vor allem danken wir ihnen dafür, dass Sie den vielen Unterstützerinnen und Unterstützern, weiterhin den jüngeren Mitarbeiterinnen und den Mitgliedern des Ehrenkomitees, den Vorstands- Mitarbeitern mit Rat und Tat zur Seite stehen. mitgliedern, dem wissenschaftlichen Beirat und unseren zahlreichen Spenderinnen und Spendern, Eine wichtige Entwicklung für die weitere die uns schon viele Jahre treu begleiten, bedanken. ■ Verstärkung unseres Instituts war die Ernennung eines neuen wissenschaftlichen Direktors. Mit Assoc.-Prof. Dr. Kaan Boztug gewinnt die St. Anna Univ.-Prof. Dr. Wolfgang Holter, Kinderkrebsforschung nicht nur einen führenden Institutsleiter Experten für angeborene seltene Erkrankungen der Blutbildung und des Immunsystems, sondern auch einen Kollegen, dem als Oberarzt in der pädiatrischen Onkologie und als Leiter der Immunologie der Klinikalltag im St. Anna Kinderspital sowie die Praxis in der Behandlung Einleitung [ 12 ] Forschungsbericht St. Anna Kinderkrebsforschung | Science Report St. Anna Children’s Cancer Research Institute Vorwort des wissenschaftlichen Direktors St. Anna Kinderkrebsforschung tatsächlich eine Herzensangelegenheit. Hier kann ich mein Wissen gezielt einsetzen und meinen Fokus auf das Wohl der Kinder richten. Am Institut arbeitet eine Gruppe von äußerst enthusiastischen Forscherinnen und ls wissenschaftlicher Direktor des Forschern, deren wichtige wissenschaftliche Instituts ist es mir eine besondere Arbeiten ich in diesem Bericht vorstellen möchte. Freude, den Forschungsbericht der St. Anna Kinderkrebsforschung mit Dank neuer Technologien wissen wir heute, dass eröffnen zu dürfen. Obwohl meine Krebserkrankungen, beispielsweise solche, die unter Ernennung erst am Ende dieser Berichtsperiode dem Überbegriff Leukämie zusammengefasst Aerfolgte, verbindet mich mit der St. Anna Kinder- werden, tatsächlich sehr unterschiedlich sind. krebsforschung bereits eine mehrjährige Geschichte: Unsere molekularbiologischen Erkenntnisse Als Oberarzt in der pädiatrischen Onkologie und erlauben heute eine zunehmend vollständigere Cha- Leiter der Immunologie am St. Anna Kinderspital rakterisierung jedes einzelnen Patienten; der Krebs sehe ich im Klinikalltag die Möglichkeiten und wird in immer feinere Subgruppen unterteilt und Grenzen in der Behandlung krebskranker Kinder, zerfällt schlussendlich in genetisch und/oder die mich stets zu noch tiefer greifenden Forschungs- epigenetisch klassifizierbare „seltene“ aktivitäten motivieren. Seit 2016 leite ich das von Erkrankungen“. Das erklärt wahrscheinlich die mir konzipierte und von der Ludwig Boltzmann schon seit langem bekannte Beobachtung, dass Gesellschaft gegründete Ludwig Boltzmann Institute Therapien bei einzelnen Patientinnen und Patienten for Rare and Undiagnosed Diseases, an dem die St. mehr oder weniger gut wirken und wir für weitere Anna Kinderkrebsforschung als Partnerinstitution Fortschritte in der Kinderonkologie teilweise dem-
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