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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
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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