Where next? A critical approach to ACGT Exploitation and Ambitions

1. Where next?A critical approach to ACGT Exploitation and Ambitions D. Kafetzopoulos FORTH-IMBB Sapporo, 14th September 2009

2. Presentation Outline • BioMedical Informatics Initiatives • Project Output Highlights • Project Exploitation & Utilization • Project Objectives & Respective Obstacles • New Challenges and Technology Needs • Emerging opportunities D. Kafetzopoulos Sapporo, 14th September 2009 FORTH-IMBB

3. BioMedical Informatics Initiatives The ACGT(EU), caBIG(US) & NCRI bioinformatics(UK) approaches: • ACGT uses a Bottom-Up approach for addressing the BMI needs of clinico-genomic research, • Explores the multi-national & multidisciplinary dimensions of the modern cancer research, • Focuses on specific technological developments being limited in scale, time, resources, strategic targeting, means for imposing solutions • Employs scenarios for capturing user needs and for specifying the development of technology • Uses “real-life” clinical data for testing and demonstration • Promotes the strategic priority of the ICT & Health themes of the EC (FP6) for the Integration of European Cancer Research. D. Kafetzopoulos Sapporo, 14th September 2009 FORTH-IMBB

4. Project Output Highlights • BMI Grid architecture addressing both data access & services • Unique ontology based clinical trial management tool incorporating a graphical trial builder and a versatile CRF editor • Data analysis services enabling complex queries and an environment workflows • Promising modeling approaches to tumor growth and therapy response simulations including multiple case viewer. • An advanced and most suitable legal and data security infrastructure for clinical research D. Kafetzopoulos Sapporo, 14th September 2009 FORTH-IMBB

5. Project Exploitation & Utilization • Approach International Clinical Research Organizations (IARC, WHO, EORTC etc) and promote the deployment of the BMI infrastructure especially in field of cancer research • Provide specific solutions to Large Clinical Trial Consortia and Medical Societies (Trans-BIG, SIOP…) • Demonstrate utility in specific needs mutual benefits for the collaboration with Pharmaceutical Industry • Allow National Health Authorities to reach the primary health care system, incorporate remote centers into the national clinical research infrastructure and enable the discovery potential of individual research laboratories • Contribute the ACGT know-how for the development of the new European Research Infrastructure (EATRIS, BBMRI etc) • Apply for new R&D funding based the existing expertise in order to expand and complete the ACGT technologies D. Kafetzopoulos Sapporo, 14th September 2009 FORTH-IMBB

6. Selected Objectives & Obstacles • Exchange of clinicogenomic data & samples (ownership & legal constrains, persisting data heterogeneity & paperwork) • Multilevel biological data integration (immaturity of post-genomic technologies, limitations in data mining & visualization tools) • Simulation Approaches & Modeling (Computational and design challenges in modeling molecular mechanisms) • Data collection for enabling future retrospective clinical trials (balance between depth & wideness of data, bioethical limitations) D. Kafetzopoulos Sapporo, 14th September 2009 FORTH-IMBB

7. New Challenges and Technology Needs • New disease subclasses & new stratification groups for promoting personalized medicine. • Large GenomeWideAssociationStudies (GWAS) and Full Genome Sequencing for the identification of uncommon-common mutations with moderate-low phenotypic penetration (T2 diabetes, hypertension, Prostate cancer…) • Gene expression technology shift from (microarray) hybridization to (2nd generation) sequencing methodologies • New layers and in multi-level organization of life and new genome analysis methods (miRNA, epigenetic maps, methylation, interactome…) • New genome browsers, new modeling and visualization tools to facilitate the understanding of genetic knowledge D. Kafetzopoulos Sapporo, 14th September 2009 FORTH-IMBB

8. Keratins 5/6, 17 Cadherin laminin UNK ERBB2 GRB7 MLN64 UNK 17q22.24 Non Epithelial CD36R GTPO G3PDH Keratins 8/18 Transferrin R UNK GATA3, XBP1 TFF1, HN3A GATA3XBP1 TFF1, HN3A LIV1 Subclass Survival 85 tissue samples, 456 genes, 5 subclasses (Therese Sørliea et al. PNAS vol. 98, 10869-10874) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications

9. The Human Genome Variations Monogenic disorder causing disease Mutations Predisposing variations Normal functional variations Polymorphisms Phenotypic penetration Rarity Multi-factorial disorders SNPs Pharmacogenomics, drug dependent Neutral (i.e. blood groups) useful genetic markers,

10. From hybridization to 2nd generation sequencing Quantitate levels of RNA expression –Better sensitivity, dynamic range, and gene coverage than any microarray -Absolute measurement of abundance VS relative signal intensity –Results can be compared to 3’-arrays, all exonarrays, and tiling arrays Transcriptome Structure and Genome Annotation –Provide EST-like information to help annotate previously sequenced genomes –Data can be used to discover novel transcripts –Study RNA Processing –Characterize more alternative transcripts Study transcriptome polymorphism –Characterize SNPs, point mutations, and insertion/deletions in mRNA –Discover disease-associated biomarkers –Quantitate aberrant expression in diseased tissues

11. The miRNA layer in tumorigenesis

12. DNA packaging, Chromatin States & Epigenetic Code Packaging ratio 10,000:1

14. Emerging opportunities for further research • The EU R&D Framework Program 7 • Cooperation • Health • ICT • Innovative Medicine Initiative • Capacities ESFRI • BBMRI • ECRIN • EATRIS • ELIXIR • SYSTEMS BIOLOGY D. Kafetzopoulos Sapporo, 14th September 2009 FORTH-IMBB

15. FP7 HEALTH Theme Combating Cancer Objectives • To develop improved patient-oriented strategies for combating cancer - from prevention, to more effective and earlier diagnosis, and better treatment with minimal side effects. Focus on • Establishing facilities and developing initiatives for the exploitation of research on cancer in Europe; encouraging the development of evidence-based guidelines for good clinical practice and improved public health strategies by accelerating the translation of existing research results into applications. • Supporting clinical research, particularly clinical trials, aimed at validating new and improved interventions. • Supporting translational research aimed at bringing basic knowledge through to applications in clinical practice and public health. • Other issues related to cancer, such as ageing and cancer, regional differences, psycho-social aspects, palliative care and guidance to support groups. Approach • Support for research that extends and builds on the knowledge created by genomics and other fields of basic research, and translates it into applications that contribute to the objectives listed above.

16. Areas covered by EU-funded cancer research Causes and mechanisms underlying cancerAlthough recent years have witnessed significant progress in understanding the transformation of a normal cell into a cancer cell, a lot remains to be discovered. The EU is committed to research on the causes and mechanisms underlying cancer, covering a wide range of topics, from the molecular causes of cancer to its development and progression, through to molecular mechanisms relevant to the discovery of new drug candidates. Cancer treatment and palliative careOne of the main objectives of EU-funded cancer research is to find better treatment with minimal side effects. The EU encourages the development of guidelines for good clinical practice and the translation of existing research results into concrete applications. As a consequence, EU funds support clinical research aimed at validating new and improved interventions as well as translational research aimed at bringing basic knowledge through to applications in clinical practice and public health. Moreover EU-funded cancer research addresses treatment resistance, side effects of cancer therapy and palliative care. Risk factors and cancer preventionUnder the Seventh Framework Programme, more than €27 million so far have been devoted to research focusing on risk-factors and prevention. Indeed, understanding the role of nutritional, genetic, environmental and socio-economic factors involved in cancer could help predict the risk of certain cancers and prevent their occurrence.

17. How does the EU contribute to the coordination of cancer research in Europe? The European cancer research field is characterised by its fragmentation and its diversity (multiplicity of support mechanisms, funding bodies, etc). Consequently, one of the EU's key policy objectives for the proposed Partnership is to improve the coordination of cancer research activities throughout Europe. This is in line with the objectives of the European Research Area (ERA) which endeavours to bring together EU, national and regional research programmes, activities and policies.The recommendations of the EUROCAN+PLUS project have been taken up in FP7 to help establish a strong, harmonised collaborative framework for cancer research in Europe. For instance, the EUROCOURSE project tackles fragmentation in the funding and usage of cancer registries in Europe, while the OPCARE9 and PRISMA actions focus on integrating knowledge and practice of end-of-life care.To further strengthen the coordination of cancer research in Europe, the European Commission will shortly launch a new call for proposals for the establishing of an ERA-Net on translational cancer research in Europe. ERA-Nets, whose name refers to the European Research Area and to Networking, are designed to coordinate the activities of national and regional research funding organisations.

18. Joint Technology Initiative on Innovative Medicines Objectives:The overall goal of the Innovative Medicines Initiative (IMI) is to reinvigorate the European bio-pharmaceutical sector thereby promoting private research and development in the sector. The IMI will also serve as a focal point for developing synergies between research and collaboration with national, European and international activities and therefore contribute to the establishment of the European Research Area (ERA) in this sector. Implementation:The main challenges to be tackled by the Innovative Medicines Initiative are: - insufficient investment in (R&D) in industry; - the technological complexity of drug innovation; - the fragmentation of research within Europe or its location outside Europe, primarily in the US or Japan.

19. Joint Technology Initiative 2009 Draft IMI JU Draft Scientific Priorities 2009The Draft Scientific Priorities 2009 have been adopted by the IMI Governing Board at itsmeeting on 20th March 2009 to set the frame for the development of call topics, which will bepublished later this year (presumably September). The Efficacy Pillar priorities for this year are: In Cancerthe focus is foreseen on the following fields: The development, evaluation and qualification of imaging biomarkers of tumor cell proliferation and death, and of the invasive phenotype is one area with the focus to create a network of imaging centres allowing clinical validation of imaging biomarkers across multiple sites.Another field in the area of cancer is the search for new tools for target validation to improved rug efficacy, including improved models and integrated bioinformatics to generate testable hypotheses (systems biology). A third field are molecular biomarkers for the acceleration of cancer therapy development and refining of patient care focusing on the characterisation of predictive, prognostic and pharmacodynamic biomarkers and the standardisation of analytical methods and data retention and sharing. In Infectious DiseasesIMI sees a strong need in the identification and development of rapid point of care diagnostic tests for bacterial diagnosis to facilitate conduct of clinical trials and clinical practice with focus on respiratory tract infections (pneumonia, bronchitis etc ). In Inflammation chronic immune mediated diseases (IMDs) are the focus for 2009. The goal is to get a better understanding of aberrant adaptive immunity mechanisms in human chronic IMDs by comparative human T-cell and B-cell biology. The primarily tackled diseases will be Rheumatoid Arthritis (RA), Systemic Lupus Erythematosis (SLE) & Inflammatory Bowel Disease (IBD). In the Knowledge Management Pillar the focus for 2009 lies on standardization, free access, interoperability and exchange of data relevant for drug discovery and development, including databases for drug/disease models and small molecules and a frame for access and exchange of clinical/healthcare data.

20. European Strategy Forum on Research Infrastructures • ESFRI, the, is a strategic instrument to develop the scientific integration of Europe and to strengthen its international outreach. The competitive and open access to high quality Research Infrastructures supports and benchmarks the quality of the activities of European scientists, and attracts the best researchers from around the world. • The mission of ESFRI is to support a coherent and strategy-led approach to policy-making on research infrastructures in Europe, and to facilitate multilateral initiatives leading to the better use and development of research infrastructures, at EU and international level. The publication of the first Roadmap for pan-European research infrastructures in 2006 was a key contributing factor, and several projects are now entering the realization phase. The first update of the ESFRI Roadmap is scheduled for release at the end of this year, in the Fifth European Conference on Research Infrastructures to be held in Paris on 9 and 10 December 2008. • To keep Europe at the rapidly evolving forefront of science and technology, and to increase the capacity to meet the needs of the EU and World scientific community, much remains to be done: ESFRI looks forward to the challenging times ahead.

21. The pan-European Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) collects human biological samples, such as blood, tissues or DNA. It also includes associated clinical and research data, as well as biomolecular research tools, which are key resources in unravelling genetic and environmental factors underlying diseases and influencing their outcome. These resources are required for identification of new targets for therapy and may help to reduce attrition in drug discovery and development. • The Biological and Medical Sciences research community relies on exchanging data and information from distributed and heterogeneous sources. One of the main challenges is to develop the infrastructures required to ensure that these data have been collected in harmonised ways and made accessible to the research communities. TheELIXIR European research infrastructure will bedeveloped to address these needs.

22. BBMRI is strongly cooperating with EATRIS, which is dealing with translational research. The translation of basic research discoveries into clinical applications, including the scientific validation of experimental results, should support a faster and more efficient transfer of research findings into the development of innovative strategies for the prevention, diagnosis and treatment of diseases of particular relevance for Europe, reducing the high medical and economic burden. • There is a strong connection of EATRIS with ECRIN as ECRIN follows EATRIS in the development chain of new therapies and diagnostics. ECRIN deals with clinical trials from phase II onwards, whereas EATRIS covers the research up to clinical trials phase II. The collaboration between both research infrastructures facilitates the transfer of innovations into improved medical care and health strategies.