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Multi-scale network biology model &          the model library      --           Jianghui Xiong 熊江辉            Laserxiong@...
Network – a better knowledge   representation system
Synthetic lethal provideapproach for drug combination
Synthetic lethal provide approach for improving targeted therapies (drug            combination)
Synthetic lethal provide approach for        personalized therapy
Network models library?• Diverse types of node    –   Gene    –   Gene modules    –   microRNAs    –   Long non-coding RNA...
Network models library?• For genetic interaction   – Different phenotype define different type of networks   – Different e...
Multi-scale networkSystems pharmacology and genome medicine: a future perspective. Genome Medicine 2009
Inter-cell network
Inter-tissue network
Inter-tissue network
A case study     Pre-Clinical Drug Prioritization via    Prognosis-Guided Genetic Interaction                   NetworksJi...
Oncology Drug DevelopmentOne of most challenging scientific problems           What’s wrong with our cancer models? NATURE...
What’s wrong with our Disease Models The current models used for pre-clinical drug testing Do NOT accurately predict how n...
SOD (Synergistic Outcome Determination)                                   Bad Outcome                              Bad Out...
SOD (Synergistic Outcome Determination)          vs Synthetic Lethality Featurecompared                  SOD      Syntheti...
The pipeline1                                                            3    Protein Network        Pathway              ...
Gene Module DatabaseProtein                            miRNA                         Gene           Pathway               ...
Prognosis Data        -- data associated gene expression with                   patients’ prognosisPrognosis Data Instance...
Module-module cooperation network                                                      Candidate                          ...
Inter-Module Cooperation Network (IMCN)for lung cancer suggests that the network robustness highly             dependent o...
Characterization of the Inter-Module Cooperation Network (IMCN)‘Gatekeeper’ modules for lung cancer (NSCLC)               ...
Contribution of various evidence sources       for gene module definition
Comparing genetic (somatic mutation) and epigenetic (DNA methylation)    aberration rate (in tumor vs. normal) of two type...
Compound action on cellsConnectivity MAPNCI 60 in vitro Drug screen Project
Compound-Gene Correlations                     Compound in vitro                                 NCI 60 panel gene        ...
Use Perturbation Index (PI) to quantify                     Drug actionHypothesis   – To disrupt/perturb cancer network, t...
Benchmarking for pre-clinical drug prioritizing• Why test?   – Assess the potential application for prioritizing compounds...
Bootstrapping-based assessment of Perturbation Indexon discriminating successful drugs from the candidate
Rank of drugs and agents in clinical development for lung      cancer according to their Perturbation Index
How to quantify synergistic effect of Drug                         Combination?      Drug       A                       Po...
The Perturbation Index ofpair-wise combination of lung cancer agents                       • Validity of Bortezomib-      ...
Bortezomib-Gemcitabine CombinationGemcitabinebaselineperturbationGemcitabineBortezomibadd a focusedperturbationon keygatek...
The Library of Network Biology Models            need your input!              Thanks!
Multi-scale network biology model & the model library
Multi-scale network biology model & the model library
Multi-scale network biology model & the model library
Multi-scale network biology model & the model library
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Multi-scale network biology model & the model library

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Multi-scale network biology model & the model library

  1. 1. Multi-scale network biology model & the model library -- Jianghui Xiong 熊江辉 Laserxiong@gmail.com
  2. 2. Network – a better knowledge representation system
  3. 3. Synthetic lethal provideapproach for drug combination
  4. 4. Synthetic lethal provide approach for improving targeted therapies (drug combination)
  5. 5. Synthetic lethal provide approach for personalized therapy
  6. 6. Network models library?• Diverse types of node – Gene – Gene modules – microRNAs – Long non-coding RNAs …• Diverse types of edge (interaction) – Physical interaction – Genetic interaction – Co-expression – Bayesian …• Various metric for target identification – Connectivity (hub) – Bridging centrality – Hierarchy…
  7. 7. Network models library?• For genetic interaction – Different phenotype define different type of networks – Different experimental methods – Different context (cell lines, tissue source..)• Biologists need pre-defined network models• “The library of Network Models” – Annotate – Benchmark/validate – Updating – Integrating
  8. 8. Multi-scale networkSystems pharmacology and genome medicine: a future perspective. Genome Medicine 2009
  9. 9. Inter-cell network
  10. 10. Inter-tissue network
  11. 11. Inter-tissue network
  12. 12. A case study Pre-Clinical Drug Prioritization via Prognosis-Guided Genetic Interaction NetworksJianghui Xiong et al. Pre-Clinical Drug Prioritization via Prognosis-Guided Genetic Interaction Networks. PLoS ONE. 2010The full text of this paper (PLoS ONE) could be download from:http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0013937
  13. 13. Oncology Drug DevelopmentOne of most challenging scientific problems What’s wrong with our cancer models? NATURE REVIEWS DRUG DISCOVERY, 2005
  14. 14. What’s wrong with our Disease Models The current models used for pre-clinical drug testing Do NOT accurately predict how new treatments will act in clinical trials – Heterogeneity in patient populations – Unpredictable physiology ? Drug Discov Today Dis Models, 2008 What’s wrong with our cancer models? NATURE REVIEWS DRUG DISCOVERY, 2005
  15. 15. SOD (Synergistic Outcome Determination) Bad Outcome Bad Outcome Gene Pair Gene Pair Gene Gene Gene Gene A B A B Good Outcome Good Outcome Gene Pair Gene Pair Gene Gene Gene Gene A B A B Synergistically Infered Nexus ( SIN ) ������������������ ������1 , ������2 ; ������ = ������ ������1 , ������2 ; ������ − ������ ������1 ; ������ + ������(������2 ; ������) ������(������, ������) ������ ������; ������ = ������ ������, ������ log 2 ������ ������ ������(������) ������ ������
  16. 16. SOD (Synergistic Outcome Determination) vs Synthetic Lethality Featurecompared SOD Synthetic LethalityPhenotype Survival outcome of Cell death/growth individual patient Level Individual Cell Data Human population Yeast (SGA);Accessible (via computation) Human cell lines; Human population
  17. 17. The pipeline1 3 Protein Network Pathway Inter-Module Gene Module Compound route of action Cooperation Gene Ontology Database Analysis Network miRNA Target Gene Prognostic Data Perturbation Index (PI) Benchmarking/Validation2 Compound in vitro screen data Gene Signature for Compound Sensitivity Drug Combination NCI 60 panel gene Simulation Expression data
  18. 18. Gene Module DatabaseProtein miRNA Gene Pathway TargetNetwork Ontology Gene Gene Module Database
  19. 19. Prognosis Data -- data associated gene expression with patients’ prognosisPrognosis Data Instance Benefit of Prognosis Dataa “wound response” geneexpression signature in predicting • Natural populationbreast cancer progression - Heterogeneity • Tumor tissue - Microenvironment reflection • Final point phenotype - Survival time • Comprehensive genomic characterization • Large Data Set Chang H Y et al. PNAS 2005;102:3738-3743
  20. 20. Module-module cooperation network Candidate Candidate Module Module Query B B ModuleGene Module A Database Candidate Module C Cooperation SIN A SIN A Module B SIN A Candidate Module Query C Module A Pool 1 Whole Gene Set (M genes) Together Gene-Gene 2 SIN analysis Gene 1 SIN A SIN A Cooperation SIN Gene list Module C ... Gene K Gene2 K For each gene SIN Gene list SIN Gene listQueryModule A
  21. 21. Inter-Module Cooperation Network (IMCN)for lung cancer suggests that the network robustness highly dependent on gatekeeper modules Gatekeeper Module Checkpoint Module
  22. 22. Characterization of the Inter-Module Cooperation Network (IMCN)‘Gatekeeper’ modules for lung cancer (NSCLC) 3 Major Biological Theme
  23. 23. Contribution of various evidence sources for gene module definition
  24. 24. Comparing genetic (somatic mutation) and epigenetic (DNA methylation) aberration rate (in tumor vs. normal) of two types of modules Top 10% or 20% of genes which highly used (i.e. one gene involved in multiple gene modules) as representative of each types of modules
  25. 25. Compound action on cellsConnectivity MAPNCI 60 in vitro Drug screen Project
  26. 26. Compound-Gene Correlations Compound in vitro NCI 60 panel gene screen data Expression data 60 cell lines 60 cell lines 22,000 genes43,000 compounds 43,000 compounds x 22,000 genes Activity (A) Targets (T) A•T′ Activity Compound/drug A’s there are a measurement of drug activity (A) cross 60 cell line is determined by GI 50 (the 50% growth inhibition values) , the concentration of the drug necessary to reduce the growth rate of cells by 50% to that of controls. Activity (A) = -log10(GI50) Sensitivity “Sensitivity” = the sensitivity of one particular cell lines to a drug. if drug d1 can effectively inhibit the cell growth of cell line c1, we say “ cell line c1 is sensitive to drug d1”
  27. 27. Use Perturbation Index (PI) to quantify Drug actionHypothesis – To disrupt/perturb cancer network, the key to success is to simultaneously perturbs the corresponding gatekeeper modules with the checkpoint modules • Hi -- the number of hits by compound c • Li -- the active links ( i.e. links in which both source node and target node are matched by compound c) • N -- the number of gatekeeper modules
  28. 28. Benchmarking for pre-clinical drug prioritizing• Why test? – Assess the potential application for prioritizing compounds for clinical trials, based on the information available in pre-clinical stage• ‘Standard Agent Database’ – Originally created by Boyd [29] and ultimately finalized by the NCI – Compounds which have been submitted to the FDA for review as a New Drug Application – OR compounds that have reached a particular high stage of interest at the NCI• Successful drug list - FDA approved and routinely used drugs• Candidate list - the remainder• Test what? – Whether we could statistically discriminate between these two compound lists using the perturbation index
  29. 29. Bootstrapping-based assessment of Perturbation Indexon discriminating successful drugs from the candidate
  30. 30. Rank of drugs and agents in clinical development for lung cancer according to their Perturbation Index
  31. 31. How to quantify synergistic effect of Drug Combination? Drug A Pool Drug DrugDrug Perturbation Together Gene list A A B PI (Union) Analysis Drug B Drug Perturbation Gene list ABDrug Perturbation Gene list B
  32. 32. The Perturbation Index ofpair-wise combination of lung cancer agents • Validity of Bortezomib- Gemcitabine – Notable survival benefits in lung cancer patients using a Bortezomib + gemcitabine/carboplatin combination as first-line treatment (phase II clinical trial reported) • Davies, A.M. et al. J Thorac Oncol 4, 87-92 (2009) • Validity of Bortezomib-Paclitaxel – In an RNA interference (RNAi)-based synthetic lethal screen for seeking paclitaxel chemosensitizer genes in human NSCLC cell line, proteasome is the most enriched gene group • Whitehurst, A.W. et al. Nature 446, 815-819 (2007)
  33. 33. Bortezomib-Gemcitabine CombinationGemcitabinebaselineperturbationGemcitabineBortezomibadd a focusedperturbationon keygatekeepermodules
  34. 34. The Library of Network Biology Models need your input! Thanks!

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