4. Systems Biology of Cancer Andrei Zinovyev Institut Curie -
INSERM U900 / Mines ParisTech Computational Systems Biology of
Cancer Stratified Medicine - Opportunities for Business Leicester -
23 January 2013
5. Institut Curie, Bioinformatics and Systems Biology of Cancer
DepartmentInstitut Curie Created in 1909 by Marie Curie From
fundamental research to innovative treatment Comprehensive Cancer
Center 2 cancer hospitals, focus on breast cancer, pediatric
tumors, uveal melanoma 15 research departments 3,000
staffComputational Systems Biology of Cancer group
(http://sysbio.curie.fr) 15 people (physicists, mathematicians,
biologists) Cancer data analysis Mathematical modeling of cancer
processes Collaborations with pharmaceutical companies
6. Example of Stratified/Personalized Medicine: SHIVA clinical
trial at Institut Curie InformedPatients with refractory
consentcancer (all tumor types) signed Tumor biopsy + Blood sample
High Throughput Sequencing Therapy based on molecular profiling -
Approved molecularly targeted agent Informed Molecular profiling
consent signed R Conventional therapy based on Molecular
oncologists choice Prospective Eligible biology cohort patient
board Cross-over Specific NO therapy YES available
7. One of the problems of personalized medicine: existence of
complex feedbacks in a cancer cellAn example of paradoxal answer to
treatment (Prahallad et al, Nature 2012)
8. HOW SYSTEMS BIOLOGY CAN HELP? (what is systems biology?) can
it be a support for rationaldecision-making in stratified
medicine?
9. Two systems biologies 2001 2002studying biological systems
by studying structure and dynamicssystematically disturbing them of
cellular and organismaland monitoring the gene, protein function,
rather than theand informational pathway characteristics of
isolated parts of aresponses and integrating these cell, with
particular emphasis ondata in mathematical models emerging system
properties such as robustnessDanger: high-throughput stamp Danger:
creating fruitlesscollection abstractions
10. Computational Systems Biology of Cancer Specific flavor of
systems biologyObject: cancer and cancer treatmentTools:1)
High-throughput data withparticular emphasis on individualgenomic
data,2) Statistical analysis in large dimensions3) Mathematical
modeling (what ifquestions)Objective: prediction of cancertreatment
success in a concrete patient(virtual tumour in virtual
patient?)
11. Computational Systems Biology of Cancer group at Institut
CurieObjective of our group: based on existing knowledge anddata,
be able to explain why certain mutations of normalgenome can lead
to tumorigenesis, and how to reversetheir effect?Tools: Formal
representation of biological knowledge (map of cancer) Mathematical
modeling (animation) of biological diagrams Mechanistic models of
epistasy (genetic interactions)
12. Cancer: hallmarks, networks and maps Task: assemble this
network at its full complexity Problems: What language to use? How
to navigate? How to maintain? Hanahan and Weinberg, 2011, Cell How
to use?
13. Towards an Atlas of Cancer Signaling Networks Atlas of
Cancer Signalling NetworksRB/E2F-Cell Cycle DNA repair-Cell Cycle
CellDesigner tool (Diagram editor for signaling networks
representation) Systems Biology Graphical Notation (SBGN) visual
syntax Calzone et al, Kuperstein et al, Mol Syst Bio 2008
unpublishedCell Survival Cell death-energy metabolism Coming: maps
of EMT, motility, Cohen et al, Fourquet et al, unpublished
unpublished polarity, immune response
14. NaviCell: Navigation and curation of Atlas of Cancer
Signaling Networks Atlas of Cancer Signalling Networks NaviCell =
Google map + Semantic zoom + BlogGoogle map Blog Semantic
zoomNaviCell: a web tool for navigation, curation and maintenance
of molecular interaction maps. http://navicell.curie.frKuperstein
I, Pook S, Cohen DPA, Calzone L, Barillot E and Zinovyev A
(submitted) [email protected]
15. Using the maps: put data on top of it
16. Pathway staining and Anna Kareninas principle 506, G1, T1,
noninvasive 1533-1, G3, T4, invasive 2307, G2, T2, invasive 870-1,
normal 3721-10, normal 915-1, normal
17. Using the maps: finding alternative routesAll path of
length