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SMBCa Systems Medicine of Breast Cancer Metastasis and Drug Resistance Preparatory meeting for BMBF e:Med program Heidelberg, December 4, 2013 agenda • Welcome • Introduction of partners and participating groups • Introduction into the BMBF e:Med program • Why breast cancer? • Presentation and discussion of individual subprojects • Open questions • Timeline • Miscellaneous • close background of e:Med • Framework program ‘Health Research 2010-2018’ of the Federal Government Key-words: • Aging population -> cancer, cardiovascular, diabetes… • New routes for prevention and treatment • Individualized medicine • Molecular mechanisms of disease • Innovation: diagnosis, therapy, early detection, prevention • Basic research >>> clinical application (“from bench to bedside”) • Systems Biology – high throughput technologies, disease models, biobanking, • Integration of key competences in Germany • Global networking: research infrastructures competitiveness BMBF – Funding environment Deutsche Zentren der Gesundheitsforschung Research Infrastructures • Neurodegenerative diseases • Diabetes • Cardiovascular diseases • Infection diseases • Translational cancer research (DKTK) • Lung diseases International commitment of BMBF ICGC, IHEC, … Project Funding NGFN (2001-2013), Systems Biology (2008-2013) e:Bio – on-going -> small Systems Biology related projects -> SysmetBC – ‘Systems biology of metabolic transformation in breast Cancer’ -> Metastasys – ‘Analysis of Molecular Markers and Pathways in Cancer Cells and Microenviroment that determine the Fate and Localization of Tumor Metastases’ e:Med – NEW – Maßnahmen zur Etablierung der Systemmedizin e:??? – more to come (this year – “demonstrator” projects towards commercialization) “map” of the BMBF e:Med Keywords • Systems Medicine – personalized treatment • Improvement of the quality of medicine • OMICs technologies – - - -> clinics • Molecular networks and their roles in pathophysiological processes • Preexisting data and materials (no large-scale gathering of new data and biomaterials/clinical studies) • Data management strategies (collection, archiving, processing, analysis, visualization, exchange) • International standards for collection and management of materials and data -> integration of data into existing collections • Systems biological modeling of pathophysiological mechanisms combined with in vivo testing • Some technology development (e.g., in vitro functional assays and animal models) • International networking – international visibility e:Med Key numbers • Funding for 3 + 2 years • Evaluation after first 2 years • 12-15 mio EURO/year • 10-20 networks with 0.5-2 mio EURO/year • Deadline: January 15, 2013 • • Targeted Systems Medicine into the clinics Targeted therapies – benefits and challenges • Combination of large-scale molecular data (sequencing, gene expression), in vitro cell biology models (large- and fine-scale), quantitative proteomics, in vivo mouse models & in vivo imaging, clinics, systems biological modeling • Breast cancer subtypes – molecular subtypes (expression profiling -> sequencing) Significantly mutated genes and correlations with genomic and clinical features. Tumour samples are grouped by mRNA subtype: luminal A (n = 225), luminal B (n = 126), HER2E (n = 57) and basal-like (n = 93). The left panel shows non-silent somatic mutation patterns and frequencies for significantly mutated genes. The middle panel shows clinical features: dark grey, positive or T2–4; white, negative or T1; light grey, N/A or equivocal. N, node status; T, tumour size. The right panel shows significantly mutated genes with frequent copy number amplifications (red) or deletions (blue). The far-right panel shows non-silent mutation rate per tumour (mutations per megabase, adjusted for coverage). The average mutation rate for each expression subtype is indicated. Hypermutated: mutation rates >3 s.d. above the mean (>4.688, indicated by grey line). DC Koboldt et al. Nature 000, 1-10 (2012) doi:10.1038/nature11412 WashU – Nature 2012 Tumor stroma interactions miR520/206 Massague Cell 2008 Division Molecular Genome Analysis mostly breast cancer (some GIST) Growth factors/ligands/ shedding-products RPPA/MIA/ELISA Signaling pathways: MAPK PI3K NF-KB TGF-b Gene-activation and feedback control mutations / miRNA interactions e.g. Haller J Pathol 2010 Epigenetics – promoter methylation e.g. Haller J Pathol in review Tumor-stroma interactions cytokines/chemokines e.g. Keklikoglou Oncogene 2012 3D-cultures co-cultures mouse models Pathway interactions siRNA/miRNA screening e.g. Sahin PNAS 2007, Zhang PLoS One 2011 Uhlmann Mol Sys Biol 2012 Protein abundance and activation quantitative proteomics/cell-based assays e.g. Uhlmann Oncogene 2010 Henjes Oncogenesis 2012 Regulation of gene expression miRNA/transcription faktor interactions e.g. Ward Oncogene 2012 Burmeister Mol Cell Biol 2012 Aims – molecular mechanisms of disease Metastasis formation miRNAs/TFs & signaling vs. molecular alterations Drug resistance Tumor – stroma interactions Basic research – systems biological modeling – clinical translation Gynecology Clinical studies Pathology: Clinical validation Epigenetic variation Metastasis Genetic variation TF/molecular Variation Networks in cancer Drug resistance quantitative Modeling Bioinformatics Transcription factor Networks of metastasis molecular Tools Data management In vivo mouse models Tumor Stroma interactions miRNA-signaling Networks SMBCa Networking How visualize relations within (and beyond) the consortium? Circos plot e:Med prerequisites (call for proposals) • Systems biology concept - quantitative, dynamic data – Stefan Legewie/Jens Timmer/ (?) • Clear disease focus - breast cancer metastasis & drug resistance & environment • Interdisciplinary research problem to be tackled - big and small data -> “systems medicine of BCa” • Coverage of all necessary disciplines - basic research … clinics • Willingness for cooperation with other research consortia - successful (joint publications) collaborations in the past • Highest quality of methods and the planned science - depends on you ! • Proven expertise of applicants - i.e. you ! • Relevance of aims for medicine and industry - no. of cases, mortality, targeted drugs • access to relevant patient- and controll collections and –materials, and clinical data in sufficient quality and quantity - Erlangen – primary tumor, metastases(?), Bavarian cancer registry w/ long-term follow-up • Equipment to carry out high-throughput analyses (sequencing, arrays, …) and internal as well as external data from high-throughput projects DKFZ facilities and ICGC, TCGA, … (IHEC?) ToDos • Outlines of individual subprojects • What can you provide? • What can others provide to you – your needs? • Connections between subprojects (internal and external) • National and international networking ToDos • expertise and previous work of the consortium partners in the research area addressed. • Proof that all necessary expertises and capacities are included. • existing resources within the consortium (e.g. established methods, phenotyped patient- and controlcollectives, equipment, material- or data libraries, HTcapacities for genotyping or sequencing etc.). • availability and access to data and/or biomaterials for the consortium. • Planned measures for quality assurance, standardisation and exchange of information, methods, samples and data. e:Med and ‘our’ background/environment (BMBF funding) 1996-2004 2001-2004 2004-2008 2008-2011 2008-2013 2008-2011 2009-2013 2013-2015 DHGP NGFN – cDNA platform -> Resources NGFN-2 – SMP-Cell -> cellular assays, protein localization NGFN-Plus – Integrated Genome Network Cellular Systems Genomics -> Breast cancer signaling NGFN-Plus – Integrated Genome Network Environmental Diseases (Stefan Schreiber) -> NF-KB signaling NGFN-Transfer Project Genome subfractionation for targeted sequencing (Hugo Katus) SysMed: Breast Sys – Identifying novel therapeutic strategies for breast cancer by data-driven modeling of tumor progression e:Bio small Systems Biology related projects -> SysmetBC – ‘Systems biology of metabolic transformation in breast Cancer’ -> Metastasys – ‘Analysis of Molecular Markers and Pathways in Cancer Cells and Microenviroment that determine the Fate and Localization of Tumor Metastases’ Plus some international collaborations Your background/environment ? To be added to the proposal: large funding programs and grants • previous projects… • ICGC • ... ? … national and international … with relation to e:Med ! ToDos • Concept for commercial or clinical exploitation – Commercial – Clinical – small-scale studies? • Ethical and legal considerations – Patient material – Patient data – Mouse models – Other? This is a 5-year program • longer time visions • Deliverables and milestones – for 2 years, 3 years and 5 years -> measurable!! Time of review End of first period End of program Timeline • • • • • • • • SW will distribute templates for subproject descriptions (today) SW will distribute first draft of global description (end of next week) Everyone will submit first (advanced) draft by Dec 12 return for revision by Dec 18 submit of second draft by Dec 28 distribution of proposal by Jan 9 for last revisions finalization of proposal by Jan 14 submission on Jan 15