Transcript New Targets

Signaling Pathways
Therapeutic Targets in Cancer
Targeting the Tumor and
Its Microenvironment
1.
2.
3.
4.
5.
6.
7.
8.
9.
Growth factor signaling
Other growth stimulating/
suppressing receptors
Microtubule dynamics
Histone acetylation/
10
deacetylation
DNA replication,
transcription, repair
Protein synthesis
Protein folding
Cell cycle
Activators and
1
inhibitors of
9
Cancer Cell
2
Tumor Cell Death
1
apoptosis
10. Metastasis
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3
6
6
7
7
1
4
8
1
8
5
Cancer Cell
Tumor Cell Growth/Replication
5
Endothelial Cell
Angiogenesis
Targets of Cancer Therapy
19
1
Plasma Membrane
16
5
2
4
6
3
7
17
18
RNA Translation
7
Growth
Factor
Signaling
7
11
8
Microtubule Dynamics
Nuclear Membrane
13
9
12
10
Gene Transcription
DNA Replication and Repair
14 15
Cell Growth Motility Survival Proliferation Angiogenesis
1.
Growth factors
2.
Growth factor receptors
3.
Adaptor proteins
4.
Docking proteins/
binding proteins
5.
Guanine nucleotide
exchange factors
6.
Phosphatases and
phospholipases
7.
Signaling kinases
8.
Ribosomes
9.
Transcription factors
10.
Histones
11.
Molecular chaperones
12.
DNA
13.
Microtubules
14.
Cyclins
15.
Cyclin-dependent
kinases
16.
Cell death receptors
17.
Apoptosis-effector
caspases
18.
Caspase inhibitors
19.
CD40-CD40L
Receptor Tyrosine Kinase (RTK) Families
and Their Activation
HER (erbB) Family
TGF-a
EGF
EGFR
None
HER2
Heregulin
Epiregulin
HER3
VEGFR Family
Heregulin
Epiregulin
VEGF-A
VEGF-B
VEGF-A
VEGF-C
VEGF-D
PDGFR Family
VEGF-C
VEGF-D
VEGFR-1 VEGFR-2 VEGFR-3
HER4
FL
PDGF
SCF
Flt-3
PDGFR
KIT
Receptor Dimerization and Activation
FGF-1–FGF-14
FGF-16–FGF-23
FGFR1
FGFR2
FGFR3
IGF-1
IGF-2
FGFR4
P
P
P
P
IGF-1R
P
P
P
P
P
P
P
P
P
P
P
P
VEGFRs, PDGFR,
KIT, Flt-3
EGFR/HER2
Mutant Flt-3
VEGF Receptors in Angiogenesis
and Lymphangiogenesis
TKI
VEGF-A, -C, -D, -E
PlGF
VEGF-A, -B
VEGF-C, -D
VEGFR-2 / KDR
VEGFR-1 / Flt-1
PI(4,5)P2
PI(3,4,5)P3
PI(4,5)P2
PI3-K
P
P
P
P
PLCg
Sck
PTEN
VEGFR-3
DAG
+
IP3
PKC
RAS
PDK1,2
Ca++
FAK
RAC
Akt/PKB
Permeability
RAF
Survival
MEK
Paxillin
ERK
Migration
Angiogenesis
Lymphangiogenesis
FGF Receptor Signaling in Tumor Cell
Growth and Angiogenesis
TKI
PI(4,5)P2
DAG
+
IP3
PKC
Grb2
SOS
P
RASGDP
PLCg
RASGTP
GTP
SHP-2
Ca++
RAF
RAF
PLA 2
Platelet-Activating Factor
MEK
MEK
ERK
JAK
ERK
Gene Expression
Apoptosis
Proliferation
Migration
Differentiation
Angiogenesis
Growth Factor Signaling Through
EGFR/HER2
EGF, TGF-α
PI(4,5)P2
PI(3,4,5)P3
PI3-K
TKI
HER2
EGFR
P
P
P
P
Grb2
SOS
P
RAS-GDP
PTEN
GTP
PDK1,2
PDK1,2
RAS-GTP
Akt/PKB
RAF
Glycogen
Synthesis
MEK
Survival
ERK
Proliferation
Migration
Cell Growth, Proliferation, Survival, Transformation
The IGF-1R Signaling Pathway
TKI
PI(4,5)P2
IGF-1R
P
P
P
P
P
PI3-K
SOS
Shc
PI(3,4,5)P3
RAS-GDP
GTP
SHP-2
IRSs
RAS-GTP
Grb2
SHP-2
PTEN
Akt/PKB
RAF
mTOR
4E-BP1
MEK
S6K1
ERK
elF-4E
Elk-1
Ribosomal Synthesis
mRNA Translation
Cell Growth, Proliferation, Survival, Transformation, Metastasis, Angiogenesis
Mutant and Wild-Type Flt-3 Activation in
Leukemic (AML, ALL) Cells
Normal
Hematopoietic Cells
TKI
Flt-3 Mutations (AML)
Flt-3-ITD
Flt-3-D835
FL
Wild-type Flt-3
MAP
Kinase
Pathway
RAS-GTP
TYK2
RAF
STAT5
Cell Proliferation
JAK/STAT
Pathway
CD40L (CD154) Stimulates
Growth and Survival of B Cells and
B-Cell–Derived Malignant Cells
CD40 Antagonist
Antibody
X
CD40L (CD154)
TRAFs
PI3-K
XX X X
NF-kB
JNK
Akt/PKB
P38
MAPK
• Inhibition of Apoptosis
• Cell Growth
• Cell Proliferation
TRAF = TNF receptorassociated factor.
B Lymphocytes
B-Cell–Derived Malignancies
ERK
Activation of RAS-RAF Oncogenes by
Mutation or Growth Factor Stimulation
EGF
EGFR
KI
HER2
RAS-GTP
RAF
Grb2
MEK
Shc
Kinases
eg, Src,
PAK
ERK
Substrates in
Cytosol
and Cytoskeleton
Elk-1
SRF
Substrates
in Nucleus
Cell Growth, Proliferation, Survival, Transformation, Metastasis, Angiogenesis
Central Role of BCR-ABL in Leukemic
Cells (CML, ALL)
IL-3
Receptor
TKI
Gab2
Shc
SOS
Grb2
PI3-K
P
RAS-GDP
GTP
RAS-GTP
JAK
RAF
BCR-ABL
Akt/PKB
MEK
SHP-1
FAK
ERK
Antiapoptosis
Paxillin
Migration
Gene Expression
Cell Growth, Proliferation, Survival, Transformation, Metastasis
Multispecific TKIs: Targeting Multiple
Growth Factor Signaling Pathways
EGFR/HER2
Cancer Cell
TKI
VEGFR
Endothelial Cell
Induction of Apoptosis
Through Death Receptors
Agonist
Antibody
Death
Receptor
Mitochondrion
Bad
Cyto C
Bid
ProCaspase
8
Bax
PI3-K
RAS-GTP
Bax
Bcl-2
FLIP
ProCaspase
3
Bcl-XL
Caspase
8
Caspase
9
IAP
ICAD
Akt/PKB
Cyto C
APAF1
ProCaspase
9
Caspase
3
CAD
PARP
Cell Death
Cross-Talk Between the PI3-K/Akt
and RAS/RAF Signaling Pathways
Cytokine
Receptor
Growth Factor
Receptor
RAS
PI3-K
RAF
Akt/PKB
MEK
ER
mTOR
ERK
mRNA
Translation
Growth
Survival
Division
Gene
Transcription
Motility
mTOR: A Central Controller of Tumor Cell
Growth and Angiogenesis
VEGF
Growth factors
VEGFR
Integrins
PTEN
Oxygen,
Nutrients,
Amino Acids
ILK
PI3-K
PI3-K
LKB1
Akt/
PKB
AMPK
Akt/
PKB
Energy
TSC1/TSC2
mTOR
Inhibitor
mTOR
4E-BP1
mTOR
Inhibitor
S6
elF-4E
X
S6K1
Protein production
X
Gene
transcription
X
mTOR
FKBP-12
FKBP-12
P
mTOR
Inhibitor
X
Cell growth
Cancer Cell
X
VEGF
production
Cell growth and
proliferation
Proliferation
Endothelial Cell
Histone Acetylation in the
Regulation of Gene Transcription
HDAC
Inhibitor
TF
DNA
Ac
Ac
HDAC
Ac
Ac
Ac
Ac
TF
Ac
Ac
Transcriptional
Repression
Histones
HAT
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Transcriptional
Activation
Oncogene
Expression
Tumor Suppressor
Gene Expression
Apoptosis
Molecular Chaperones
and Protein Folding
ADP
ADP
Protein
Function/
Confirmation
HSP90
Inhibitor
HSP90
HSP90
HOP
p23
Early complex
HSP40
Final complex
HSP70
X
HSP90
Propylisomerase
s
Protein Degradation
HSP40
HSP40
HSP70
HSP70
p23
HOP
HSP90
HSP90
Propylisomerase
s
HOP
Intermediate complex
R. Jensen modified from Wegele et al. Rev Physiol Biochem Pharmacol. 2004;151:1-44, © Springer-Verlag GmbH
Cell Cycle Regulation by Cyclins and
Cyclin-Dependent Kinases (CDKs)
Dephosphorylation
G0
Cyclin
B
Restriction
Point
CDK1
M
CDK
Inhibitor
Cyclins
Cyclins
D1, D2,
D3
G1
CDKs
CDK4
CDK6
G2
Cyclin
A
Proteasomal
Degradation
Protein
Synthesis
CDK
Inhibitor
S
Cyclin
E
CDK1
CDK2
Cyclin
A
CDK
Inhibitor
CDK
Inhibitor
p21
p27
others
CDK2
Modified from Schwartz and Shah. J Clin Oncol. 2005;23:9408-9421, with permission.
Topoisomerase I Inhibition Induces
DNA Breaks and Cell Death
Topoisomerase I Inhibitor
DNA
Polymerase Topoisomerase I
5'
5'
5' 3'
Replication
Fork
5'
Replication
Fork
TOPO
I
TOPO
I
Replication
Replication
DNA
Ligase
3'
5'
Replication
Fork
3'
3'
3'
5'
3'
TOPO
I
• Replication fork
encounters stabilized
Topo I DNA complex
• Replication stops
5' 3'
5'
TOPO
I
• DNA single-strand breaks
• Cell death
3'
Microtubule Dynamics as a
Target of Cancer Therapy
Microtubules
Depolymerization
G2
Microtubule
Stabilizer
S
Microtubule
Dynamics
Mitosis
Polymerization
Cell Death
G1
Rational Combinations:
Proven Therapies and New Targets
• Proven therapies
– Growth factor receptors and downstream signaling kinases
– Cytotoxic chemotherapy
– Radiation therapy
– Hormonal therapy
• Multiple new targets
– Cell metabolism, cell growth, protein translation, protein folding
– Gene transcription
– Cell cycling, DNA replication, and cell division
– Cell death receptors
– Tumor neovasculature