pre-clinical drug prioritization via prognosis-guided genetic interaction networks
DESCRIPTION
presentation on IDDST 2010 by Jianghui XiongTRANSCRIPT
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In silico Genetic Network Models for Pre-clinical Drug Prioritization
Jianghui Xiong 熊江辉[email protected]
http://cn.linkedin.com/in/jianghuixionghttp://www.researchgate.net/profile/JIANGHUI_XIONG/
October 23, 2010
Section 2-1: Genomics, Proteomics and Metabolomics in Drug Discovery and Target Validation
Click to get the full text paper (PLoS ONE): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0013937
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Network pharmacology
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The information to deliver
• Network could be drug target
• Jianghui Xiong etc., Pre-clinical drug prioritization via prognosis-guided genetic interaction networks. PloS ONE 2010
• “For more than a decade, scientists in systems biology have promised that real breakthrough in genetic medicine will come when we stop mapping individual genes to phenotypes and instead start looking at interacting networks. Yet, not much has happened. The field is still struggling to define relevant networks and to interpret data in terms of those networks.
The paper by Xiong et al adds considerably to the progress of network-based genetic medicine. It is highly relevant, original and interesting.”
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Oncology Drug DevelopmentOne of most challenging scientific
problems
What’s wrong with our cancer models? NATURE REVIEWS DRUG DISCOVERY, 2005
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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
What’s wrong with our cancer models? NATURE REVIEWS DRUG DISCOVERY, 2005
What’s wrong with our Disease Models
Drug Discov Today Dis Models, 2008
?
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Hypothesis– Considering gene networks associated with cancer
outcome in heterogeneous patient populations – The difficulty of identify effective cancer cures (as
evidenced by drug resistance) may be a consequence of the robustness of this network
– Network (robustness) as drug target
Pre-clinical in silico Cancer Models for Drug action study
– Incorporating heterogeneity and in vivo physiology information, which MISSING in pre-clinical cancer models
Our proposal1
2
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SOD (Synergistic Outcome Determination)
Bad OutcomeGene Pair
Gene A
Gene B
Bad OutcomeGene Pair
Gene A
Gene B
Good OutcomeGene Pair
Gene A
Gene B
Good OutcomeGene Pair
Gene A
Gene B
Synergistically Infered Nexus ( SIN )𝑆𝑦𝑛ሺ𝐺1,𝐺2;𝐶ሻ= 𝐼ሺ𝐺1,𝐺2;𝐶ሻ − ሾ𝐼ሺ𝐺1;𝐶ሻ+ 𝐼(𝐺2;𝐶)ሿ
𝐼ሺ𝑋;𝑌ሻ= 𝑝ሺ𝑥,𝑦ሻlog2 𝑝(𝑥,𝑦)𝑝ሺ𝑥ሻ𝑝(𝑦)𝑦𝑥
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SOD (Synergistic Outcome Determination) vs Synthetic Lethality
Feature compared SOD Synthetic LethalityPhenotype Survival outcome of
individual patientCell death/growth
Level Individual Cell
Data Accessible
Human population(via computation)
Yeast (SGA);Human cell lines;Human population
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The pipeline
Protein NetworkPathway
Gene OntologymiRNA Target Gene
Gene ModuleDatabase
Prognostic Data
Inter-ModuleCooperation
Network
1
Compound in vitro screen data
NCI 60 panel geneExpression data
Gene Signature forCompound Sensitivity
Compound route of action Analysis
Perturbation Index (PI)Benchmarking/Validation
Drug CombinationSimulation
2
3
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What is Gene Module? And Why We use it instead of the single
genes?Gene Module: a group of genes which share similar function
ab
cd
e f
Gene Module 1
x A single gene
……
Gene Module 2
Gene Module 3
Gene Module 4
Gene Module n
……
Gene Module:robust/reproducible features rather than single genes
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Gene Module Database
ProteinNetwork
Pathway
Gene Ontolog
y
miRNA Target Gene
Gene ModuleDatabase
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Chang H Y et al. PNAS 2005;102:3738-3743
a “wound response” gene expression signature in predicting breast cancer progression
• Natural population - Heterogeneity• Tumor tissue - Microenvironment reflection• Final point phenotype - Survival time• Comprehensive genomic
characterization• Large Data Set
Prognosis Data -- data associated gene expression with
patients’ prognosis
Benefit of Prognosis Data Prognosis Data Instance
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Gene ModuleDatabase
Module-module cooperation network
K
12
...
For each geneQuery
ModuleA
Gene KSIN Gene
list
Gene2SIN Gene
list
Who
le G
ene
Set (
M g
enes
)
Gene-GeneSIN analysis
Candidate Module
B
Candidate Module
C
Gene 1 SIN Gene list
SIN AQuery
ModuleA
SIN A
Candidate Module
C
SIN ACooperation
ModuleC
SIN A
Candidate Module
B
SIN A
Query Module
A
Cooperation Module
B
PoolTogether
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Inter-Module Cooperation Network (IMCN) for lung cancer suggests that the network robustness
highly dependent on gatekeeper modules
GatekeeperModule
CheckpointModule
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Characterization of the Inter-Module Cooperation Network (IMCN)
‘Gatekeeper’ modules for lung cancer (NSCLC)
3 Major Biologica
l Theme
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Contribution of various evidence sources
for gene module definition
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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
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Compound action on cells
NCI 60 in vitro Drug screen Project
Connectivity MAP
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Use Perturbation Index (PI) to quantify Drug action
Hypothesis– 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
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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
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Bootstrapping-based assessment of Perturbation Index on discriminating successful drugs from the candidate
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Rank of drugs and agents in clinical development for lung cancer according to their Perturbation Index
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How to quantify synergistic effect of Drug Combination?
Drug A
Drug PerturbationGene list A
Drug B
Drug PerturbationGene list B
Drug A
Drug PerturbationGene list AB
Drug B
PoolTogether(Union)
PIAnalysis
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The Perturbation Index of pair-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)
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Bortezomib-Gemcitabine Combination
Bortezomib
add a focused perturbation on key gatekeeper modules
Gemcitabine
baseline perturbation
Gemcitabine
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Discussion (1)As a preclinical in silico modeling tool
– Mirroring drug behavior on natural populations– Cost-effectiveness– Easy to integrate drug action
mechanisms/patterns
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Discussion (2) Strategy against cancer
• Gatekeeper modules as rate-limiting steps in therapeutic treatment Drug metabolism and accessibility Microenvironment immune system modulation
• Epigenetic plasticity on gatekeeper modules could exploited by tumor for attaining resistance to treatment
– Drug accessibility <- Multi Drug Resistance – Microenvironment <- Inflammatory– Immune modulation <- Complement activation
• Battle against cancer• know the history of tumorigenesis <etiology>• know future survival strategy of tumor under
therapeutic interventions• Systems biology modeling could provide
prediction of the tumor survival strategy
Etiology-based strategy Prediction-based strategy
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A new perspective to understand principle of drug combination in
Traditional Chinese Medicine ?
• 君 - King• 臣 - Minister• 佐 - Assistant• 使 - Ambassador
The Inter-Module Network
Different Roles of the Gene Modules& their cooperation effects