SMBCa - Systems Medicine of Breast Cancer Metastasis and Drug Resistance
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Transcript of SMBCa - Systems Medicine of Breast Cancer Metastasis and Drug Resistance
SMBCa-
Systems Medicine of Breast CancerMetastasis and Drug Resistance
Preparatory meeting forBMBF 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 GovernmentKey-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 GesundheitsforschungResearch Infrastructures• Neurodegenerative diseases• Diabetes• Cardiovascular diseases • Infection diseases• Translational cancer research (DKTK)• Lung diseases
Project FundingNGFN (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)
International commitmentof BMBF
ICGC, IHEC, …
“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)
DC Koboldt et al. Nature 000, 1-10 (2012) doi:10.1038/nature11412
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).
WashU – Nature 2012
Massague Cell 2008
Tumor stroma interactions
miR520/206
Growth factors/ligands/shedding-productsRPPA/MIA/ELISA
Tumor-stroma interactionscytokines/chemokinese.g. Keklikoglou Oncogene 2012
Protein abundance and activationquantitative proteomics/cell-based assayse.g. Uhlmann Oncogene 2010
Henjes Oncogenesis 2012
Pathway interactionssiRNA/miRNA screeninge.g. Sahin PNAS 2007,
Zhang PLoS One 2011Uhlmann Mol Sys Biol 2012
Regulation of gene expressionmiRNA/transcription faktor interactionse.g. Ward Oncogene 2012
Burmeister Mol Cell Biol 2012
Gene-activation and feedback controlmutations / miRNA interactionse.g. Haller J Pathol 2010
Epigenetics – promoter methylatione.g. Haller J Pathol in review
3D-culturesco-culturesmouse modelsSignaling pathways:
MAPKPI3KNF-BTGF-
Division Molecular Genome Analysismostly breast cancer
(some GIST)
Aims – molecular mechanisms of disease
Metastasisformation
Drug resistanceTumor – stroma
interactions
miRNAs/TFs & signaling
vs.molecular alterations
Basic research – systems biological modeling – clinical translation
Metastasis Drug resistance
Tumor Stroma interactions
miRNA-signalingNetworks
Transcription factorNetworks of metastasis
Bioinformatics
quantitativeModeling
Epigenetic variation Genetic variation
TF/molecular VariationNetworks in cancer
In vivo mousemodels
Pathology:Clinical validation
GynecologyClinical studies
molecularTools
Data management
SMBCaNetworking
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 control-collectives, equipment, material- or data libraries, HT-capacities 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 DHGP2001-2004 NGFN – cDNA platform -> Resources2004-2008 NGFN-2 – SMP-Cell -> cellular assays, protein localization2008-2011 NGFN-Plus – Integrated Genome Network
Cellular Systems Genomics -> Breast cancer signaling2008-2013 NGFN-Plus – Integrated Genome Network
Environmental Diseases (Stefan Schreiber) -> NF-KB signaling2008-2011 NGFN-Transfer Project
Genome subfractionation for targeted sequencing (Hugo Katus)2009-2013 SysMed: Breast Sys – Identifying novel therapeutic strategies
for breast cancer by data-driven modeling of tumor progression2013-2015 e:Bio small Systems Biology related projects
-> SysmetBC – ‘Systems biology of metabolic transformation in breast Cancer’
-> Metastasys – ‘Analysis of Molecular Markers and Pathwaysin Cancer Cells and Microenviroment that determine theFate 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