Angiogénèse: cible de nouvelles molécules en cancérologie .

Angiogénèse:
cible de nouvelles
molécules en
cancérologie .
ARMAND
Jean–Pierre
Directeur médical
IGR&D
Institut Gustave
Roussy
Villejuif
France
Les régionales de cancérologie
Bordeaux oct 2006
Leonardo da Vinci
CELL CYCLE INHIBITORS
• flavopiridol
• cdki
(BMS387032, roscovitine)
SIGNAL TRANSDUCTION
INHIBITORS
• HER Faimily:
Growth factor Ab (C225,
APOPTOSIS MODULATORS
• anti-bcl2
Herceptin)
Tyrosine kinase inhibitors
(OSI, ZD1839)
• PI3K pathway: mTORi
(CCI779, RAD001…)
•PKC inhibitors (eg,
ISIS3521)
• Farnesyl transferase
inhibitors (SCH66336,
R115777, BMS214662)
•PDGFR and c-kit inhibitors
(STI 571)
• ONYX-015
• RPR/IGN Adp53
• Survivin
• TRAILagonists
ANTI-ANGIOGENIC
ANTI-INVASIVE AGENTS
• Antibodies:
VEGF (Avastin)
Integrins (Vitaxine,
EMD12974…)
•
• MMP inhibitors
• Modulators of chemokines
• SMALL
MOLECULES:
•
Anti-telomerase
Telomere interacting agents
•Carcinogenesis is a multi-step process
intervention
and their receptors
• Src inhibitors
and Cure will require multispecific
ANGIOGENESE
LE MONDE 05/98 plantu
multi cibles
les monoclonaux,les inhibiteurs de TKI mono ou
Regulation of Angiogenesis
Pro-angiogenic
factors
Cytokines
VEGF
bFGF
PDGF
IL-8
EPO
IGF
TGF α, β
Enzymes
TP
MMPs
Anti-angiogenic proteins
Protein fragments
Endostatin
Angiostatin
Histidin rich
glycoprotein
Inhibitory proteins
Platelet factor-4
IFN α, β
Thrombospondin
TIMP
Soluble receptors
s-VEGF-R
s-FGF-R
VEGF: a Central Mediator of Tumor Vasculature
Development and Maintenance
EGF
IL-8
IGF-1
bFGF
Other functions of VEGF
• Monocyte chemotaxis
• DC maturation
• AML blast survival
Increased expression
(MMP, tPA, uPA, uPAr,
eNOS, etc.)
PDGF
H2O2
HIF
COX-2↑
↑
NO↑
↑
Oncogenes↑
↑
VEGF release
VEGF
Survival
Vasodilation
P
P
P
P
Binding and activation
of VEGF receptor
Proliferation Migration
ANGIOGENESIS
Permeability
Targeting the VEGF Pathway
1. Ligand Sequestration:
mAbs, Soluble Receptors
BEV, VEGF-TRAP
GW786034,
AZD2171
P
P
PTK787
3. Tyrosine Kinase
Inhibitors
2. Anti-Receptor
mAbs
5. VEGFR
Antisense/Ribozyme
RAS
MAPK
P
P
Grb2
PI3K
Src
AKT
4. Inhibitors of Downstream
signaling events
Transcription
The mamouths
Antibodies
Rapid discovery process.
Expensive and difficult to make.
Generics difficult to introduce.
IV requiring expert administration.
Potential immunogenicity.
Currently can only access external targets.
Rituximab – targets CD20 in B cell lymphomas
Trastuzumab - targets ErbB2 in breast cancer
Cetuximab – targets ErbB1 in colorectal cancer and head and neck cancer
Bevacizumab – binds to VEGF preventing it from binding to the VEGF
receptor
RhuMAb VEGF (Recombinant Humanized
Monoclonal Antibody to VEGF)
Humanized to avoid
immunogenicity (93% human,
7% murine)
Recognizes all isoforms of
vascular endothelial growth
factor, Ka = 8 x 10-10 M
Terminal half life 17-21 days
Phase III Trial: RhuMAb-VEGF in
Metastatic Colorectal Cancer (First Line)
IFL = FL/BV (3rd arm prem. closed),
Hurwitz H et al. Proc ASCO 2003, late breaking
Hurwitz et al. JCO 2005
Phase III Trial: Paclitaxel + Carboplatin
+/- Bevacizumab in
NSCLC Non-Squamous (First Line)
Overall Survival
Progression Free Survival
BREAST Progression-free Survival
1.0
Avastin + paclitaxel: 11.4 months
Paclitaxel: 6.11 months
PFS proportion
0.8
HR=0.51 (0.43-0.62)
Log rank test: p<0.0001
0.6
0.4
0.2
6.11
0
0
484 events reported (89%
of required events)
11.4
6
12
18
Time (months)
24
30
Miller KD, et al. BCRT 2005;94 (Abstract 3)
Combination Trials
Regimen
Bevacizumab + IFN vs. IFN
Status
Phase III intergroup
Bevacizumab + Erlotinib
(33 % OR)
Phase II complete (VICC+SCCC)
Randomized Bevacizumab
+/- Erlotinib
Phase II underway
Bevacizumab + Erlotinib +
Imatinib
In development (NCI-Surgery, CWG)
Bevacizumab + IL2
In development
(VICC+Penn+DF/HCC)
BAY 43-9006 + Bevacizumab
BAY 43-9006 + CCI-779
Concept to CTEP (DF/HCC+VICC)
Phase II randomized
In development (VICC + SCCC)
VEGF-Trap, How It Works
Aptamer
VEGF Ab
(Avastin®)
VEGF
VEGFR-2 Ab
VEGF Trap
TK Inhibitors
VEGFR-2
VEGF
VEGF Trap:
Trap:aafusion
fusionprotein
proteinof
ofdomains
domains
from
fromVEGF
VEGFReceptors
Receptors11and
and22with
withIgG
IgGFc
Fc
All
Allhuman
humanamino
aminoacid
acidsequences!
sequences!
~110,000
~110,000MW
MW
Kd
Kd<<11pM
pM
Blocks
BlocksVEGF
VEGFin
inall
allmammalian
mammalianspecies
species
(and
also
blocks
PLGF)
(and also blocks PLGF)
Observed
Observedhalf
halflife
lifein
inhumans
humans~~17
17days
days
Sanofi Aventis
Oncology
The Tumor Vascular Disrupting Agent
AVE8062
Water-soluble derivative of combretastatin
M eO
M eO
OMe
N H C O C H (N H 2 )C H 2 O H
HCl
OMe
Combretum caffrum
AVE8062A
Tubulin polymerization inhibitor
Depolymerizes microtubules
Colchicine binding site
Activity on proliferating microvascular endothelial
cells
Cytotoxic to tumor cells
The Foxes:
Small Molecules
Long discovery process but specific SAR can be
chemically engineered.
Relatively simple and cheap to make.
Patient convenience – usually oral.
Compliance might be an issue.
Can access internal targets in the cell.
Imatinib – targets Bcr-Abl in CML and c-kit in GIST (and
probably PDGFRA)
Gefitinib – targets EGFR in NSCLC, H&N cancer and glioma
Erlotinib – targets EGFR in NSCLC and glioma
Bayer 43 – multitargets VEGFR Raf
Sugen11258 – multitargets VEGFR
Many VEGF Inhibitors in
Clinical Development
Tumor Type
EGFR
PDGFR
VEGFR
FGFR
FLT3
CHIR-258 Ph1
SU-11248 Ph3
BAY 43-9006 Ph3
RTK
reported
to be
inhibited
PTK-787 Ph 3
ZD-6474 Ph 2
ZD-2171
AEE778 Ph 1
AMG-706 Ph 1
AG-13736 Ph 2
XL 999 Ph 1; (IV)
BIBF 1120
RTK not
reported
to be
inhibited
PTK/ZK:
An Oral Multi-VEGF Receptor Inhibitor
Potent inhibitor of all known
VEGF receptors
Also inhibits PDGFR and c-Kit
Half life of 3 to 6 hours
Oral once-daily dosing
Fit of PTK/ZK (green)
into the ATP binding site
Phase III: FOLFOX 4 +/- PTK in
Metastasized Colorectal
Cancer: Negative
Multinational Randomized Phase III Trials
Previously
untreated patients
(N=1,168)
Confirm 1
R
A
N
D
O
M
I
Z
E
D
PTK/ZK 1,250 mg/day p.o.
+ oxaliplatin/5-FU/LV IV q 2 weeks
Placebo
+ oxaliplatin/5-FU/LV IV q 2 weeks
Patients pre-treated for
recurrent CRC with
CPT-11 based therapy
N=855
Confirm 2
R
A
N
D
O
M
I
Z
E
D
PTK/ZK 1,250 mg/day p.o.
+ oxaliplatin/5-FU/LV IV q 2 weeks
SU11248 Blocks Key RTK Targets
Antiangiogenic effects
PERICYte
PDGFA
Antitumor effects
VASCULAR
ENDOTHELIAL CELL
Tumor CELL
VEGFB
VEGFA
VEGFD
PDGFB
VEGFC
Mutated
PDGFR-α
α
receptor
Mutated
KIT
receptor
PDGFR-β
β
SU11248
VEGFR-1 VEGFR-2 VEGFR-3
SU11248
Inhibition of:
Pericyte proliferation
Endothelial cell proliferation
Tumor growth
SU11248
SU11248
Reversible Hair Depigmentation Likely
to Result from KIT Inhibition
Sutent in GIST resistant to glivec:
TTP and OS by Treatment
100
80
70
60
50
40
30
20
80
70
60
50
40
30
20
10
10
0
0
0
10
20
30
40
50
SU11248
Placebo
90
Estimated Survival Probability (%)
90
Estimated TTP Probability (%)
100
SU11248
Placebo
60
Time (Weeks)
The analysis was based on the Interim Analysis dataset.
Kaplan Meier curves are marked at each censoring time.
Median TTP placebo: 1.5 m
Median TTP SU11248: 6.3m
P = 0.00001
0
10
20
30
40
Time (Weeks)
The analysis was based on the Interim Analysis dataset.
Kaplan Meier curves are marked at each censoring time.
P = 0.0067
50
60
Progression Free Survival Probability
Sutent in RCC
Progression-Free Survival
1.0
Sunitinib
Median: 11 months
(95% CI: 10–12)
0.9
0.8
IFN-α
α
Median: 5 months
(95% CI: 4–6)
0.7
0.6
0.5
0.4
0.3
0.2
Hazard Ratio = 0.415
(95% CI: 0.320–0.539)
P <0.000001
0.1
0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
Time (Months)
No. at Risk Sunitinib:
No. at Risk IFN-α:
235
152
90
42
32
18
2
0
14
Two Types of Response Observed in RCC
1-Shrinkage
2-Central Necrosis
Week
0
Week
0
Week
32
Week
12
Phase I Molecular and Biological Evaluation of rhuMAb-VEGF
Antibody
A Determination of tumor endothelial
permeability (MR images of the liver).
A metastasis (yellow arrow) in the
liver before therapy.
B
After treatment with rhuMab-VEGF.
100
0.3 mg/kg
80
% maximum
permeability
60
1-10 mg/kg
40
20
0
Day 0
Jayson GC et al. J Natl Cancer Inst 2002; 94: 1484-1494.
Day 2
Day 35
SU11248 Control of Imatinib-Resistant
GIST in a Patient with Primary
Resistance to Imatinib
Baseline
Day 7 PET
Normal
heart
Normal
kidneys
CT after
2 months
of
SU11248
Demetri GD et al. Proc Am Soc Clin Oncol 2005 (Abstract 4000)
What about Doppler- ultrasonography ?
1996 to 2006 ….
Main recent evolutions
ultrasound contrast agents
Technical developments :
perfusion softwares with information processing :
quantification softwares : calculating parameters of perfusion :
quantitative analysis
Dynamic Contrast Enhanced–US (DCE-US)
Baseline
High-Resolution
WeekHigh-Frequency
1
Color Doppler Ultrasound Sonography
MOLECULAR TARGETED
THERAPY
Courtesy of Dr. Nathalie Lassau
• A morphologic study with a 20-MHz probe
OF CANCER
• Intratumoral vessels using a 13-MHz
probe
AJR Am J Roentgenol 2002
Jun;178(6):1547-51
Week 2
Week 3
No Evidence of
intratumoral
vascularisation
Large area of
intratumoral
necrosis
Limited
vascularization
surrounding the
tumor
Present Perfusion - Analysis
Peak Intenisty : Blood Volume
• Quantitative analysis of contrast uptake curve
• From Raw data and after automatic modelization
Mean transit time : MTT
Vmax
Raw data
modelization
Vmax / 2
V0
Time (s)
0
TL
Tmax
Time to peak intensity,
the slope: Blood Flow
120
Phase I : Sugen
at 50, 75 and 100 mg /day
US results as a surrogate endpoint to resonse?
Observe dose dependant effect on vascularisation
Absence of vascularization at :
7 days for 100 mg
21 days for 75 mg
6 weeks at 50 mg
Apparition of necrosis from 2 weeks :
Only for 75 and 100 mg
Modification of vascularization for one patiente according to the
modification of the dose to the toxicity
BAY 43-9006
Anticancer cell activity (cancer cells)
Inhibition of Raf kinase in signal transduction
pathway
Antiangiogenic activity (endothelial cells)
Inhibition of Raf kinase
Inhibition of VEGF and PGDF RTK
F
F
F
O
Cl
O
O
N
H
N
H
N
H
N
Sorafenib:
Kidney Cancer PFS Benefit*
Proportion of patients progression free
1.00
Median PFS
Sorafenib = 24 weeks
Placebo = 12 weeks
0.75
Hazard ratio (S/P) = 0.44
p-value <0.000001
0.50
0.25
Sorafenib
Placebo
Censored
observation
0
0
6
12
18
24
36
48
Time from randomization (weeks)
*Independently assessed
54
60
66
RESULTS
RESULTS ::
American
Oncology
American Society
Society of
of Clinical
Clinical Oncology,
Oncology,, May
May 2005
2005
A total of 87 DCE-US were performed in 30 patients
BR
GR
Before Tt
BR
GR
After 3
Weeks
(SORAFENIB)
(SORAFENIB)
Freedom free progression
and
Disease free survival
of good and poor responders
with decrease > 15% in contrast uptake at Day 14
ASCO 2006
MOLECULAR TARGETED
THERAPY
Baldness
Blindness
OF CANCER
Stroke
Cancer
Angiogenesis contributes to
more than
70 disorders
Heart ischemia
Fracture
Limb ischemia
Arthritis
Uterus
Obesity
Jain R, Carmeliet P. Sci Am 2001
Carmeliet P. Nature Med 2003;9:653–63