1. StratifiedMedicineOpportunitiesforBusiness 24th January2013

2. Session3 ApplicationsandCaseStudies 14:00SystemsBiologyinCancer DrAndreiZinovyev,Institut Curie,Paris 14:20SingleMoleculeImagingTechnology ProfessorGeorgeFraser,UniversityofLeicester 14:35KnowledgeEngineeringforBiomedical Research DrJonathanTedds,UniversityofLeicester 14:50ApplicationsinanSMEEnvironment DrKevinSlater,PetScreen Ltd

3. SystemsBiologyinCancer DrAndreiZinovyev Institut Curie,Paris

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) navicell@curie.fr

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