St. Anna Kinderkrebsforschung – Integrated and Standardized NGS Workflows for Personalised Therapy

St. Anna Kinderkrebsforschung – Children’s Cancer Research Institute

Short Name: CCRI

Country: AT

Website: www.science.ccri.at

Organization description:

The CCRI was founded in 1988 with the overall aim to improve the treatment options for children suffering from cancer through basic and translational research. The CCRI is closely affiliated with the St. Anna Children’s Hospital (the largest clinical haemato- oncological centre for the treatment of childhood cancer in Austria) and with Labdia Labordiagnostik GmbH (spin-off SME). Currently, the CCRI has 16 research groups focusing on a number of immune-therapeutic approaches and on a selected spectrum of paediatric oncological diseases such as Leukaemia, Neuroblastoma, Ewing Sarcoma, Osteosarcoma, Wilms’ tumor, Lymphoma, Langerhans cell histiocytosis and secondary diseases relevant in immunocompromised patients such as mycosis and viral infections. The Clinical Trial Unit for Studies & Statistics for Integrated Research & Projects (S²IRP) is an important link between the CCRI laboratory research activities and the clinical application of trials at the St. Anna Children’s Hospital. Essentially, S2IRP fosters clinical research in paediatric oncology by coordinating and facilitating international clinical trials.

The CCRI/St. Anna Children’s Hospital is the coordinator of the European Reference Network on Paediatric Cancer (ERN-PAEDCAN), one of the 24 European Reference Networks (ERNs) that are virtual networks involving healthcare providers across Europe. They aim to facilitate discussion on complex or rare diseases and conditions that require highly specialised treatment, and concentrated knowledge and resources. In particular, (ERN-PAEDCAN) aims at reducing inequalities in childhood cancer survival by providing high-quality, accessible and cost-effective cross-border healthcare to children and adolescents with cancer, regardless to where they live. This network gathers some of the most influential stakeholders from 18 European Countries in the field of paediatric oncology.

The CCRI is also a member of the European Joint Programme on Rare Diseases (EJP-RD). This is a 5-year programme co-funded by the European Commission that brings over 130 institutions from 35 countries to improve the integration, the efficacy, the production and the social impact of research on RD. EJP RD fosters the development, demonstration and promotion of Europe/world- wide sharing of research and clinical data, resources and know-how.

Currently, the CCRI is engaged in 9 projects funded nationally and 9 projects financed by the European Union.

Expertise:

The CCRI has developed into the largest centre for research related to childhood cancer in Austria. Our comprehensive approach bundles all fields of childhood cancer research within a permanent cycle: basic, translational and clinical research, the improvement of diagnostic and prognostic methods, and immunological therapies. The CCRI is the international trial coordinating centre in 3 main areas: ALL stem cell transplantation (ALLSCT FORUM trial); Langerhans cell histiocytosis (LCH IV trial ); and high-risk neuroblastoma (HR-NBL1/SIOPEN trial, LTI Trial).

Facilities:

The Children´s Cancer Research Institute CCRI (38.000 sq. ft.) in Vienna, is fully equipped with state-of-the-art instrumentation for nucleic acid and protein work. It is supported with shared cell culture (290 sq. ft.), core flow cytometry unit (FACS Aria, Fortessa, LSR II), fluorescent, confocal and high content imaging (Leica SP8 WLL and DM6B, VAST, Operetta), I- FISH, , zebrafish (including Biometra COPAS sorter), HD SNP array, bioinformatics facilities, and centralized administrative, ordering, and purchasing services. Additional state-of-the-art equipment that can be used free of charges includes fluorescent western blot imaging (LI-COR), real-time PCR machines (Applied Biosystems, Perkin Elmer), Amaxa Nucleofector systems (Lonza), and S5 Versa Analyzer. Through close collaborations and partnerships, the lab has access to a dedicated sequencing facility at the CeMM only one block away from the CCRI, and to mouse facilities at the LBI-CR.

Other European projects:

Active projects:

ERN-PAEDCAN (739538) Coordinator – Paediatric Rare Tumours Network – European Registry (EU 3HP)
iDysChart (820074) Leader – Charting key molecules and mechanisms of human immune Dysregulation (H2020)
PARTNER (777336) Participant – ERN-PAEDCAN Partner: Paediatric Rare Tumours Network – European Registry (EU 3HP)
EJP RD (825575I Participant – European Joint Programme on Rare Diseases (H2020)
ITCC-P4 (116064) Participant – ITCC Pediatric Preclinical Proof Of Concept Platform (H2020)
EURO EWING (602856) Consortium Participant – International Clinical Trials to Improve Survival from Ewing Sarcoma (FP7)

Finalized projects:

ONTHETRRAC Coordinator – Overcoming Neuroblastoma Tumour HETerogeneity, Resistance and RecurrAnCe (FP7)
FUNGITECT (602125) Coordinator – Optimized Diagnostics for Improved Treatment Stratification in Invasive Fungal Diseases (FP7)
ExPO-r-Net (2013 12 07) Coordinator – European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment (3HP)
INTREALL (278514) Participant – International study for treatment of childhood relapsed ALL 2010 with standard therapy, systematic integration of new agents, and establishment of standardized diagnostic and research (FP7)
PANCARESURFUP (257505) Participant – PanCare Childhood and Adolescent Cancer Survivor Care and Follow-up Studies (FP7)
ENCCA (261474) Coordinator – The European Network for Cancer Research in Children and Adolescents (FP7)

Role in the project:

The CCRI is responsible to lead work package 2 of this project, which is dedicated to the specification of medical, technical, regulatory and health economic requirements for NGS for routine diagnostics in Paediatric & Adult Oncology. The CCRI will be responsible to lead the design and implementation of the stakeholders’ and open market consultation processes with the aim of delivering the PCP template with common procurement specifications and a joint procurement agreement. Consequently, the CCRI will be actively involved in the downstream work packages 3 (Creation of specific calls for tenders) and 4 (Implementation of contracts), including the process to select suppliers and in the evaluation of their performance.

In addition, the CCRI will also be actively involved in work packages 5 (Stakeholders’ engagement, Communication, dissemination and Exploitation of project results), 6 (Ethics, data privacy and security) and 7 (Development of the specific NGS requirements in the standardisation activities for routine diagnostics with specific EQA developed).

Key personnel:

Professor Ruth Ladenstein

Professor Ruth Ladenstein (female), MD, MBA, cPM is Head of the Studies and Statistics Department at the CCRI and a senior consultant in the St. Anna Children’s Hospital. She is currently the project coordinator of the ERN PaedCan (European Reference Network for Paediatric Cancer) and the ExPO-r-Net (European Expert Paediatric Oncology Reference Network for Diagnostics and Treatment, 2014 – 2017) project and coordinated the ENCCA (FP7 funded European network of for Cancer Research in Children and Adolescents) project. Furthermore, Prof. Ladenstein previously managed the EC FP5 funded project SIOPEN-R-NET. She is chief investigator of the high-risk neuroblastoma trial (HR-NBL-1/SIOPEN) with over 2000 patients enrolled. She is past president of SIOPEN (SIOP Europe Neuroblastoma Group; 2007- 2011) and past president of SIOPE (2009- 2012) and head of the Austrian Paediatric Oncology Group (AGPHO). She has 106 full publications in peer-reviewed journals and 13 published book chapters as first author. Prof. Ruth Ladenstein will co-lead WP2 together with Prof. Kaan Boztug.

Assoc. Prof. Kaan Boztug

Assoc. Prof. Kaan Boztug (male), MD is Scientific Director of the CCRI and a senior consultant at St. Anna Children’s Hospital, and holds a dual appointment as Associate Professor at the Department of Paediatrics and Adolescent Medicine. He is Co-Director of the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Adjunct PI at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, and Director of the Jeffrey Modell Diagnostic & Research Center Vienna, and the CeRUD Vienna Center for Rare and Undiagnosed Diseases (both located at the Medical University Vienna). His research focuses on the identification and molecular in-depth study of novel genetic etiologies of rare haemato-oncological diseases and bone marrow failure syndromes, and rare monogenic disorders of the immune system and haematopoieses. With his team he has made numerous seminal contributions to the field, having resulted in over 90 articles and reviews in peer-reviewed journals, including the discovery of several novel nosological entities published in renowned journals like The New England Journal of Medicine, Nature Genetics, and others. He has been granted a number of high-ranking research grants and prizes, including a START Prize by the Austrian Science Fund FWF and an ERC Starting Grant (both 2012), and an ERC Consolidator Grant in 2018. Prof. Kaan Boztug will co- lead WP2 together with Prof. Ruth Ladenstein.

Professor Thomas Lion

Professor Thomas Lion (male), MD, PhD, MSc is head of the Department of Molecular Microbiology at the Children´s Cancer Research Institute and Medical Director of Labdia, an associated facility focused on the development and performance of molecular diagnostics in the areas of cancer and related infectious diseases. He and his team have made major contributions to both research and diagnostics of Ph-positive leukaemias, and serve as a European (EUTOS) diagnostic reference centre in this field. Prof. Lion has been coordinator or participant in numerous international projects funded by the European Commission, and has been serving as member of a number of international research and diagnostic boards. His research is documented by more than 160 publications in international journals and several text books, for which he served as editor or contributed chapters. He has obtained patents for different technical developments and received 19 international and national research awards.

Starting Grant (both 2012), and an ERC Consolidator Grant in 2018. Prof. Kaan Boztug will co- lead WP2 together with Prof. Ruth Ladenstein.

Eleni M. Tomazou

Eleni M. Tomazou (female), PhD is a PI at the CCRI aiming to establish an epigenome-based precision medicine program for pediatric sarcomas. She did her PhD at the Wellcome Trust Sanger Institute (Cambridge, UK), and her postdoctoral training at the Broad Institute and the Harvard Department for Stem Cell and Regenerative Biology (Cambridge, USA). She is a recipient of the Elise Richter Fellowship, a prestigious career deveopment program for female scientists offered by the Austrian Science Foundation (FWF). She is a member of the Ewing Sarcoma Biology Committee of the Children’s Oncology Group.

Sabine Taschner-Mandl

Sabine Taschner-Mandl (female), PhD is currently a senior scientist and will be PI (from 11/2018) of the Tumour Biology Group at CCRI. She is secretary of the SIOPEN Biology Group and currently co-/coordinating national and international translational research projects including the FFG funded VISIOMICS (2017-2019) developing a platform for data analysis in diagnostics and the WWTF funded targetUHR (2019-2022) which aims to identify and therapeutically exploit combinatorial targets of ultra-high-risk Neuroblastoma.

Haimel Matthias

Haimel Matthias (male), PhD is the Bioinformatics Project Leader for Personalized Medicine at the Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD). He did his PhD at the University of Cambridge Department of Medicine analysing whole genome sequence (WGS) data from 13,000 rare disease patients do elucidate the underlying genetic cause. He is currently developing sequencing strategies at the LBI-RUD, co-/coordinating international projects to improve the clinical specification for diseases of immune dysregulation, participating in the European Joint Programme on Rare Diseases (RJP-RD) and developing an NGS data analysis platform for diagnostics.

Nuno Andrade

Nuno Andrade, (male), PhD, MBA is the head of the Research Support Office at the CCRI. He oversees the administrative management, implementation and reporting of the national and international grants running at the CCRI. He is experienced in the establishment of project management and procedures and contributed to numerous cooperative initiatives to acquire international-funded projects.

Ana Pudja

Ana Pudja, (female), PhD is a project manager at the CCRI. She did her PhD at CeMM – Research Center for Molecular Medicine of the Austrian Academy of Sciences, with focus on cancer research and genetics (including NGS). With a scientific background and a certificate from the International Project Management Association (IPMA) she is working as a project manager of H2020 projects.

Main publications and patents:

Publications:

Ladenstein R, Pötschger U, Valteau-Couanet D, Luksch R, Castel V, Yaniv I, Laureys G, Brock P, Michon JM, Owens C, Trahair T, Chan GCF, Ruud E, Schroeder H, Beck Popovic M, Schreier G, Loibner H, Ambros P, Holmes K, Castellani MR, Gaze MN, Garaventa A, Pearson ADJ, Lode HN. Interleukin 2 with anti-GD2 antibody ch14.18/CHO (dinutuximab beta) in patients with high-risk neuroblastoma (HR-NBL1/SIOPEN): a multicentre, randomised, phase 3 trial. Lancet Oncol. (2018); 19(12):1617-1629. doi: 10.1016/S1470- 2045(18)30578-3.

Byrne J, Alessi D, Allodji RS, Bagnasco F, Bárdi E, Bautz A, Bright CJ, Brown M, Diallo I, Feijen EAML, Fidler MM, Frey E, Garwicz S, Grabow D, Gudmundsdottir T, Hagberg O, Harila-Saari A, Hau EM, Haupt R, Hawkins MM, Jakab Z, Jankovic M, Kaatsch P, Kaiser M, Kremer LCM, Kuehni CE, Kuonen R, Ladenstein R, Lähteenmäki PM, Levitt G, Linge H, LLanas D, Michel G, Morsellino V, Mulder RL, Reulen RC, Ronckers CM, Sacerdote C, Skinner R, Steliarova-Foucher E, van der Pal HJ, de Vathaire F, Vũ Bezin G, Wesenberg F, Wiebe T, Winter DL, Falck Winther J, Witthoff E, Zadravec Zaletel L, Hjorth L. The PanCareSurFup consortium: research and guidelines to improve lives for survivors of childhood cancer. (2018) Eur J Cancer;103:238-248. doi: 10.1016/j.ejca.2018.08.017.

Ladenstein R, Pötschger U, Pearson ADJ, Brock P, Luksch R, Castel V, Yaniv I, Papadakis V, Laureys G, Malis J, Balwierz W, Ruud E, Kogner P, Schroeder H, de Lacerda AF, Beck- Popovic M, Bician P, Garami M, Trahair T, Canete A, Ambros PF, Holmes K, Gaze M, Schreier G, Garaventa A, Vassal G, Michon J, Valteau-Couanet D; SIOP Europe Neuroblastoma Group (SIOPEN) (2017). Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR- NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol.18(4):500-514.

Kager L, Jimenez Heredia R, Hirschmugl T, Dmytrus J, Krolo A, Müller H, Bock C, Zeitlhofer P, Dworzak M, Mann G, Holter W, Haas O, Boztug K (2018) Targeted mutation screening of 292 candidate genes in 38 children with inborn haematological cytopenias efficiently identifies novel disease-causing mutations. Br J Haematol. 2018 Jul;182(2):251- 258. doi: 10.1111/bjh.15389.

Salzer E, Cagdas D, Hons M, Mace EM, Garncarz W, Petronczki ÖY, Platzer R, Pfajfer L, Bilic I, Ban SA, Willmann KL, Mukherjee M, Supper V, Hsu HT, Banerjee PP, Sinha P, McClanahan F, Zlabinger GJ, Pickl WF, Gribben JG, Stockinger H, Bennett KL, Huppa JB, Dupré L, Sanal Ö, Jäger U, Sixt M, Tezcan I, Orange JS, Boztug K. (2016) RASGRP1 deficiency causes immunodeficiency with impaired cytoskeletal dynamics. Nat Immunol. 2016 Dec;17(12):1352-1360. doi: 10.1038/ni.3575

Boztug K, Järvinen PM, Salzer E, Racek T, Mönch S, Garncarz W, Gertz EM, Schäffer AA, Antonopoulos A, Haslam SM, Schieck L, Puchałka J, Diestelhorst J, Appaswamy G, Lescoeur B, Giambruno R, Bigenzahn JW, Elling U, Pfeifer D, Conde CD, Albert MH, Welte K, Brandes G, Sherkat R, van der Werff Ten Bosch J, Rezaei N, Etzioni A, Bellanné- Chantelot C, Superti-Furga G, Penninger JM, Bennett KL, von Blume J, Dell A, Donadieu J, Klein C. (2014) JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. Nat Genet. 2014 Sep;46(9):1021-7. doi: 10.1038/ng.3069

Abbasi MR, Rifatbegovic F, Brunner C, Mann G, Ziegler A, Pötschger U, Crazzolara R, Ussowicz M, Benesch M, Ebetsberger-Dachs G, Chan GCF, Jones N, Ladenstein R, Ambros IM, Ambros PF. Impact of Disseminated Neuroblastoma Cells on the Identification of the Relapse-Seeding Clone. (2017) Clin Cancer Res. 2017 Aug 1;23(15):4224-4232. doi: 10.1158/1078-0432.CCR-16-2082. Epub 2017 Feb 22.

Rifatbegovic F, Frech C, Abbasi MR, Taschner-Mandl S, Weiss T, Schmidt WM, Schmidt I, Ladenstein R, Ambros IM, Ambros PF. Neuroblastoma cells undergo transcriptomic alterations upon dissemination into the bone marrow and subsequent tumor progression. (2017) Int J Cancer. 2017 Sep 16. doi: 10.1002/ijc.31053.

Sheffield NC, Pierron G, Klughammer J, Datlinger P, Schönegger A, Schuster M, Hadler J, Guillemot D, Lapouble E, Freneaux P, Champigneulle J, Bouvier R, Walder D, Ambros IM, Hutter C, Sorz E, Amaral AT, Álava Ed, Schallmoser K, Strunk D, Rinner B, Liegl- Atzwanger B, Huppertz B, Leithner A, Pinieux Gd, Terrier P, Laurence V, Michon J, Ladenstein R, Holter W, Windhager R, Dirksen U, Ambros PF, Delattre O, Kovar H, Bock C#, Tomazou EM#. DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nature Medicine. 2017 Mar;23(3):386-395

Byrgazov K, Lucini CB, Valent P, Hantschel O, Lion T. BCR-ABL1 compound mutants display differential and dose-dependent responses to ponatinib. Haematologica. 2018 Jan;103(1):e10-e12. doi: 10.3324/haematol.2017.176347

Byrgazov K, Lucini CB, Berkowitsch B, Koenig M, Haas OA, Hoermann G, Valent P, Lion T. Transposon-mediated generation of BCR-ABL1-expressing transgenic cell lines for unbiased sensitivity testing of tyrosine kinase inhibitors. Oncotarget. 2016 Nov 22;7(47):78083-78094. doi: 10.18632/oncotarget.12943

Standards:

The PanCareSurFup consortium: research and guidelines to improve lives for survivors of childhood cancer. Byrne J, Et al. Eur J Cancer. 2018 Nov;103:238-248. doi: 10.1016/j.ejca.2018.08.017.

Bone sarcomas: ESMO-PaedCan-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Casali PG, Et al; ESMO Guidelines Committee, PaedCan and ERN EURACAN. Ann Oncol. 2018 Oct 1;29(Supplement_4):iv79-iv95. doi: 10.1093/annonc/mdy310.

The ‘Survivorship Passport’ for childhood cancer survivors. Haupt R, Et al, Ladenstein R; PanCareSurFup, ENCCA Working Group; ExPo-r-Net Working Group. Eur J Cancer. 2018 Oct;102:69-81. doi: 10.1016/j.ejca.2018.07.006.

IT Infrastructure for Merging Data from Different Clinical Trials and Across Independent Research Networks. Hayn D, Et al. Stud Health Technol Inform. 2016;228:287-91.