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Systems Biology of Tumor Progression and Drug-Resistance
COLUMBIA UNIVERSITY CENTER FOR:
CancerTarget Discovery and Development
CTD2 Network
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The Road to Drug Development
CTD2 Network
Broad
CSHL
ColumbiaDanaFarber
UT South-western
ClinicalTrials
Hit compoundMechanism
of Action
Biomarkers:Response/Efficacy
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How many tumor types are there?
(Epi-)Genetic Alterations
Subtype Signature
Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008 Oct 23;455(7216):1061-8
Verhaak RG et al.; The Cancer Genome Atlas Research Network. Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010 Jan 19;17(1):98-110
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Changing the model
Cell Dynamics
Genetics
EpigeneticsHuman Cancer
LymphoidGlioblastoma
ProstateBreast
Ovarian…
CellRegulatory
Logic
ProteinProtein
ProteinMembrane
ProteinDNA
The Harsh Reality of Cancer Genetics
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GBM (Epi)Genetic Alteration SpectrumG1 G2 G3 G4
G5 G6 G7 G8
G10 G11 G12
Patient X
MolecularPhenotype
E.g. GBM subtypes
G9
X
Y Z
W
V
MasterRegulatorModule(s)
DiseaseStratificationBiomarkers
Therapeutic Targets
…
= EGFR= PDGFRA= p16= p53= PTEN= MDM2= MDM4= MYC= NF1= ERBB2= RB1= CDK4
G1
G2
G3
G4
G5
G6
G7
G8
G9
G10
G11
G12
Glioblastoma: Carro MS et al. The transcriptional
network for mesenchymal transformation of brain tumours. Nature. 2010 Jan 21;463(7279):318-25.
Master Regulators: C/EBP + Stat3
Diffuse Large B Cell Lymphoma: Compagno M et al. Mutations of
multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature. 2009 Jun 4;459(7247):717-21
Master Regulator: Nf-kB pathway
GC-Resistance in T-ALL: Real PJ et al. Gamma-secretase
inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med. 2009 Jan;15(1):50-8.
Master Regulator: NOTCH1 pathway
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Identify and validate tumor-acquired Gene and Pathway Dependencies (Oncogene/Oncopathway addiction)
Identify their Small-Molecule Modulators
Characterize their associated Biomarkers of Response
Characterize their associated Biomarkers of Treatment Efficacy
Characterize the Mechanism of Action of their small-molecule modulators
Oncogene(s) Addiction
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POST-TRANSLATIONAL INTERACTIONS
TRANSCRIPTIONAL INTERACTIONS
Zhao X et al. (2009) Dev Cell. 17(2):210-21.Mani KM et al. (2008) Mol Syst Biol. 4:169Palomero T et al., Proc Natl Acad Sci U S A 103, 18261 (Nov 28, 2006).Margolin AA et al., Nature Protocols; 1(2): 662-671 (2006)Margolin AA et al., BMC Bioinformatics 7 Suppl 1, S7 (2006).Basso K et al. (2005), Nat Genet.;37(4):382-90. (Apr. 2005)
Wang K, Saito M, et al. (2009) Nat Biotechnol. 27(9):829-39Zhao X et al. (2009) Dev Cell. 17(2):210-21.Wang K et al. (2009) Pac Symp Biocomput. 2009:264-75.Mani KM et al. (2008) Mol Syst Biol. 4:169Wang K et al. (2006) RECOMB
POST-TRANSCRIPTIONAL INTERACTIONS
Basso et al. Immunity. 2009 May;30(5):744-52Klein et al, Cancer Cell, 2010 Jan 19;17(1):28-40.
MASTER REGULATORS AND MECHANISM OF ACTION
Lefebvre C. et al (2010), Mol Syst. Biol, in pressCarro MS et al. (2010) Nature 2010 Jan 21;463(7279):318-25Mani K et al, (2008) Molecular Systems Biology, 4:169
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Unsupervised clustering of 76 high grade tumors by expression of 108 genes that are positively or negatively associated with survival reveals 3 tumors classes (Proneural (PN), Mesenchymal (Mes) and Proliferative (Prolif).
Phillips et al., Cancer Cell, 2006
Malignant gliomas belonging to the mesenchymal sub-class express genes linked to the most aggressive properties of glioblastoma (migration, invasion and angiogenesis).
Mesenchymal Subtype of High-Grade Gliomas
MGES
PNGES
PROGES
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Mes signature genesActivatorRepressor
Identification of a mesenchymal regulatory module
Biochemical Validation of ARACNe Inferred Targets of Stat3, C/EBPb, FosL2, and bHLH-B2
Master Regulators control >75% of the Mesenchymal Signature of High-Grade Glioma
Hierarchical Regulatory Module
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C/EBPb and Stat3 modulate mesenchymal lineage in mouse neural stem cells and human glioma cells
02468
101214161820
Rela
tive m
RN
A le
vel
VectorStat3CC/EBPβStat3C+C/EBPβ
a cb
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- +Mitogens
e
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- +Mitogens
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***
***
- +Mitogens
0
20
40
60
80
100
Ctg
f + cells(
%o
f G
FP+ c
ells)
Vector
Stat3C+C/EBPβ
Vector Stat3C+C/EBPGFP GFP
CTGF CTGF
GFP/CTGF GFP/CTGF
25mm**
Figure 8
00.20.40.60.8
11.21.41.6
Rela
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shCtrshStat3shC/EBPβshStat3+shC/EBPβ
j
0
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20
30
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Co
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)
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Fib
ron
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shCtrshStat3shC/EBPβshStat3+shC/EBPβ
**
***
***
***
**
0
2
4
6
8
10
12
YK
L40
+cells (%
)
shCtrshStat3shCebpbshStat3+shCebpb
****
0
5
10
15
20
YK
L40+ c
ells (%
)
shCtrshStat3shC/EBPβshStat3+shC/EBPβ
**
*
*
a
e
shCtr shStat3 shC/EBPβ shStat3 + shC/EBPβFibronectin/DAPIFibronectin/DAPIFibronectin/DAPI Fibronectin/DAPI
Cola51/DAPICola51/DAPICola51/DAPI Cola51/DAPI
YKL40/DAPIYKL40/DAPIYKL40/DAPI YKL40/DAPI
Cola51/DAPICola51/DAPICola51/DAPI Cola51/DAPI
YKL40/DAPIYKL40/DAPIYKL40/DAPI YKL40/DAPI
shCtr shStat3 shC/EBPβ shStat3 + shC/EBPβ
25mm
25mm
25mm
100mm
200mm
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100
Cu
mu
lati
ve S
urv
ival
Days post-injection
80
60
40
20
0120806040 100
**
Control VectorStat3-C/EBPb-Stat3-/C/EBPb-
Human
MouseMouse immunohistochemistry
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Significantly Altered
Not Altered
Pathway-Wide Association Study (PWAS)
Other (56)Poor Prognosis (Mesenchymal + Proliferative) (174)
MES signature
CEBPb/d
HMG20B, PTPRAInferred via MINDY and functional association of CNVs
Inferred via ARACNE and functional association of CNVs with change in mRNA levels
TEAD3, ZFP36L2
KLHL9
Inferred via functional association of CNVs with change in mRNA levels, increase in CEBPD regulon activity
Odd Ratio = 5.405, p-value = 1.12e-6
Mutation CHR OR p-value #samples
CEBPD (amp) 8 4.61 1e-4 36
PTPRA (amp) 20 4.78 0.032 10
HMG20B (amp)
19 2.83 0.042 16
KLHL9 (del) 9 4.70 0.018 32
Mutation CHR OR p-value
C/EBPd (amp) TF Master Regulator 8 4.61 0.004
PTPRA (amp) MINDy Modulator of C/EBP subunits (YP) 20 4.78 0.032
HMG20B (amp) MINDy Modulator of C/EBP subunits (TF) 19 2.83 0.042
KLHL9 (del) Ubiquitin Conjugating Ligase. Modulates TEAD3, which is a Transcriptional Activator of C/EBP subunits
9 4.70 0.018
Gene
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Focal Amplification of C/EBPd locus
CEBPD EFCAB1 PXNDNL
Mesenchymal Non-Mesenchymal
CEBPD EFCAB1
Red: amplificationBlue: deletion
KLH
L9
MLL
T3
CDKN
2A
ELAV
L2
-log(
p) a
ssoc
iatio
n w
ith M
ES
Position (MB)
RRA
GA
FAM
29A
AD
FP
DEN
ND
4C
RPS6
ASA
H3L
SLC2
4A2
MLL
T3
KIA
A17
97
PTPL
AD
2
IFN
B1
IFN
W1
IFN
A14
KLH
L9
IFN
A2
IFN
A8
IFN
E1
MTA
P
CDKN
2A
CDKN
2B
DM
RTA
1
ELA
VL2
Pro
ne
ura
lM
es
CDKN2AKLHL9
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The Network Address of a compound
DHFR
Both Mtx and PdxPdx Only
Mtx Only
Top 2028
Network-based Activity Signature for Methotrexate and Pralatrexate (both are DHFR inhibitors): NetMoA
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CTD2: Cancer Target Discovery and Development Network
Systems Pharmacology at Columbia University
A Califano (PI), R. Dalla-Favera, A. Ferrando, A. Iavarone, B. Stockwell, J. Silva
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Collaboration with the Broad Institute (S. Schreiber) Identification of Small-molecule inhibitors of Stat3 and C/EBP
Collaboration with UT Southwestern (M. White, J. Minna) Validation of synergistic oncopathway dependencies in tyrosine kinase signaling
networks, in Non Small Cell Lung Cancer
Collaboration with Dana Farber (B. Hahn, L. Chin, R. DePinho) and the Broad Institute (S. Schreiber) Identification and validation of oncopathway addiction in ovarian cancer
Collaboration with CSHL (S. Powers, S. Lowe) Prioritization of genetic aberrations as drivers of oncogenesis in ovarian cancer
from Genome Wide Association Studies
Network Collaborations
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Parallel discovery pipeline Target(s) + small-molecule
modulators + biomarkers + MoA
Integrated, State-of-the-Art Technological Platforms RNAi + Systems Biology +
Chemistry + HT Screening + Functional Genomics
Direct Path to Translation
Large-Scale functional datasets in vitro and in vivo
Complete, network-validated data + model + reagent sharing
Investigator Network Excellence
CTD2 Conclusions
Linear discovery pipeline
Individual Technological Platform
Potential for Translation
Small Individual functional datasets
Partial data sharing
Investigator Excellence
CTD2 ModelTraditional Discovery