SMBCa - Systems Medicine of Breast Cancer Metastasis and Drug Resistance Preparatory meeting for...

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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

Transcript of SMBCa - Systems Medicine of Breast Cancer Metastasis and Drug Resistance Preparatory meeting for...

Page 1: SMBCa - Systems Medicine of Breast Cancer Metastasis and Drug Resistance Preparatory meeting for BMBF e:Med program Heidelberg, December 4, 2013.

SMBCa-

Systems Medicine of Breast CancerMetastasis and Drug Resistance

Preparatory meeting forBMBF e:Med program

Heidelberg, December 4, 2013

Page 2: 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

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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

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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, …

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“map” of the BMBF

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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

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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

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• 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)

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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).

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WashU – Nature 2012

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Massague Cell 2008

Tumor stroma interactions

miR520/206

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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)

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Aims – molecular mechanisms of disease

Metastasisformation

Drug resistanceTumor – stroma

interactions

miRNAs/TFs & signaling

vs.molecular alterations

Basic research – systems biological modeling – clinical translation

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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

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SMBCaNetworking

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How visualize relations within (and beyond) the consortium?

Circos plot

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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?)

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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

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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.

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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

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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 !

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ToDos

• Concept for commercial or clinical exploitation– Commercial– Clinical – small-scale studies?

• Ethical and legal considerations– Patient material– Patient data– Mouse models– Other?

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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

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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