gordon jayson manchester uk · 2008-01-25 · aif parameter model roi stats anti-vegf ab humv833...
TRANSCRIPT
IMAGING ANGIOGENESISGordon JaysonManchester UK
Angiogenicfactors
Cytokines•VEGF•FGF•HGF•HB-EGF•Angiogenin•IL-8•PDGF
Enzymes•TP
Anti-Angiogenicproteins
Protein fragments•endostatin•angiostatin
Inhibitory proteins•PF4
Soluble receptors•s-flt•s-FGF R
REGULATION OF ANGIOGENESIS
LungSandler NEJM 2006
CRCHurwitz NEJM 2004
LiverLlovet, ASCO 2007
BreastMiller ECCO 2005
RenalYang NEJM 2003
VEGFi INCREASE RR, PFS +/-OS IN SOLID TUMOURS
Who?Schedule?How Long?
NEW AND FUTURE TARGETS
Integrins
CNTO 95 Mullamitha, Clin Cancer Res 2007
CilengitideReardon, ASCO 2007
1
10
100
1000
1 10 100 1000 10000total tumour volume (ml)
vasc
ular
ised
vol
ume
(ml)
1 2 3 4 5 6 7 8
Jayson JCO 2005
PDGF: CP-868,596 Lewis, ASCO 2007
Sarcoma, Spindle Cell, NSCLC
NEW AND FUTURE TARGETS
IntegrinsPDGF: CP-868,596 Lewis, ASCO 2007
Ang: AMG 386 (Ang 1, 2) Rosen ASCO 2007
Ovarian
HGF: ARQ 197 (c-met RTKi) Garcia ASCO 2007
XL880 (c-met, VEGFR2 RTKi) Eder ASCO 2007
Prostate, NET, Testicular
VDAs Combretastatin
CT MetronomicCNTO 95
Mullamitha, Clin Cancer Res 2007Cilengitide
Reardon, ASCO 2007
Ridgeway, Nature 2006
DLL4 NeuropilinFGFs
ANTI-VASCULAR COMBINATION REGIMENS
VEGF, DLL4Ridgeway, Nature 2006
PBS MTD CT MET CT MTD CT MET CTVEGF RTKi VEGF RTKi VEGF RTKi
Docetaxel, AEE778HeyA8 cell line VEGF, Cytotoxic
Kamat et al., Cancer Res 2007
VEGF, FGFCasanovas Cancer Cell 2005
Time (s)
Signal(T1) Amplitude
Time to 90% max
MITRMax. gradient
VEGF - VEGF +
KtransEndothelial permeability surface area product
IMAGING THE VASCULATURE
PHARMACODYNAMIC/ BIOMARKER IMAGING OF ANGIOGENESISJayson JNCI 2002
% m
ax. p
erm
eabi
lity
0.3 mg/kg
1-10 mg/kg
0
20
40
60
80
100
Day 0 Day 2 Day 35
-80-70-60-50-40-30-20-10
010
BL-C1 BL-C4 BL-C7
KtransKepVe
PROOF THAT VEGF IS INHIBITED IN PATIENTSWedam JCO 2006
BL-C1 BL-C4/7Ki-67 2.1 -35.1MVD -14.6 16.6VEGF-A -50.0 -44.9pVEGFR2 -69.2 -88.9pVEGFR2 -66.7 -76.4VEGFR2 69.7 -28.3TUNEL 128.9 72.7
ANTI-VEGF AbINHIBIT THE
VASCULATUREWillett Nat Med 2004
Bevacizumab 5mg/kgDays 0 and 12
Flow Volume Permeability
MVD Pericytes IFP
FDG-PET CEPs CECs
Δ DCE-MRI PROPORTIONAL TO DOSE OF VEGFi
AUC (ng.h/ml)
60
40
20
0
20
40
60
80
1000 600 1000 1600 2000 2600
% c
hang
e IA
UC
60
AZD2171Drevs (ASCO 2007)
AG-013736Liu (JCO 2005)
BIBF1120Mross ASCO 2005,
PTK/ZKMorgan JCO 2003 Thomas JCO 2005
AG-013736 Plasma 24 hours AUC (ng.h/ml)
806040200
-20-40-60-80
-100
Cha
nge
in K
tran
s(%
)
10 100 1000 10000
Δ DCE-MRI IS RELATED TO OUTCOME
Reductions of >50% Ktrans are associated with stabilization
Relationship between Ktrans and PFS reported with Sorafenibin renal cancer (O’Dwyer ASCO 2005)
PTK/ZKMorgan JCO 2003Thomas JCO 2005
Baseline MRI ki (day 2: %)
Tum
or S
ize
Cha
nge
by D
ay 5
6 (%
)
100
80
60
40
20
0
-20
-40
-60
Tum
orTu
mor
Tum
orTu
mor
Tum
orTu
mor
Tum
orTu
mor
-50
-25
0
25
50
75
liver
sple
enr.k
idne
yl.k
idne
yao
rtaf.a
rterie
slu
ngth
yroi
dbr
ain
PET PKdays 2-3
VASCULAR HETEROGENEITYJayson, JNCI, 2002
AIF Parameter Model ROI StatsAnti-VEGF AbHuMV833Jayson 2002 Manual Ktrans, Kfp, Vp Tofts, ET Entire tumor Mean +/-SDBevacizumabOvermoyer 2004 KepBevacizumabDoshi 2005 Ktrans, Kp, Ve, IAUGC Brix, Kety Enhancing reg Base, single ΔBevacizumabWedam 2006 Ktrans, Kep, Ve Brix
VEGF RAZD2171Drevs 2005 IAUGC DecreaseCDP791Jayson 2006 Standard Ktrans, Vp, Ve, flow Entire tumor
VTV, IAUGCVEGFR/PDGFR TKiSU5416Medved 2004 Not required IAUGC, washout, Heuristic ΔMeanSU5416O’Donnell 2005 Cmax, Ktrans, Ve NS Pixel based MedianPTK/ZK Morgan 2003 Standard Ki Larsson Section ΔbaselinePTK/ZK Yung 2003 Ki, CBV NS ΔMeanPTK/ZK Mross 2005 Standard Ki Larsson Entire tumor ΔbaselinePTK/ZK Thomas 2005 Ki Larsson Entire tumor ΔMeanAG013736Liu 2005 Rijpkema Ktrans, IAUGC Tofts, Heur Entire tumor ΔMeanBAY 43-9006O’Dwyer 2005 Manual Ktrans Tofts Δbaseline
VEGFR/PDGFR/FGFR TKiSU6668Xiong 2004 IAUGC, slope Heuristic CT ΔbaselineBIBF1120Mross 2005 Ktrans, IAUGC Δbaseline
Anti-PDGFRβCDP860Jayson 2005 Standard Ktrans, Ve, Vp, flow, Tofts, ET, Entire tumor Median, mean
VTV, IAUGC LL HeurAnti-IntegrinCNTO95Jayson 2005 Standard Ktrans, Ve, Vp, flow, Tofts, ET Entire tumor Median, mean
VTV, IAUGC LL, Heur
EndostatinEder 2002 Manual Ktrans, Ve Tofts Entire tumor
Perfusion in pulmonary metastasis from renal cancer
STATISTICAL ANALYSIS OF DATA IS PROBLEMATIC
From Liu JCO 2005
VASCULAR PARAMETERS, HETEROGENEITY AND PROGRESSION
0
0.05
0.1
0.15
0.2
0.25
0
0.04
0.08
0.12
0.16 0.2
0.24
0.28
0.32
0.36
More
IAUC (mMOl.min)
norm
alis
ed fr
equa
ncy
ProgressiveStable/better
§ § § § † § §
IAUC
0
0.05
0.1
0.15
0.2
0.25
0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 moreVe
norm
alis
ed fr
equa
ncy
ProgressiveStable/better
§ † * § §§§ # * §
Ve
0
0.05
0.1
0.15
0.2
0.25
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9more
Ktrans (/min)
rela
tive
frequ
ency Progressive
Stable/better
§ § § †§ § §
§ p ≤ 0.001
† p ≤ 0.005
# p ≤ 0.01
* p ≤ 0.05
Ktrans
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0
0.04
0.08
0.12
0.16 0.2
0.24
0.28
0.32
0.36More
Vp
norm
alis
ed fr
equa
ncy
ProgressiveStable/better
† * § * # # †
Vp
BASELINE ENHANCING FRACTION PREDICTS OUTCOME IN OVARIAN CANCERO’Connor, Clin Cancer Res (In press)
[18F]-FLT: BIOMARKER FOR BEVACIZUMAB IN GLIOMAChen, JCO 2007
VASCULAR PERMEABILITYJayson JNCI 2002
INTERSTITIAL PRESSUREWillett, Nat Med 2004
NORMALISATIONWinkler, Cancer Cell, 2004
THE VEGF FAMILY AND ITS RECEPTORS
– P– PP–
P–
– P– P
P–P–
– P– P
P–P–
VEGF-AVEGF-B
PlGF
VEGFR-1
VEGF-AVEGF-C
VEGFR-2
VEGF-CVEGF-D
VEGFR-3
Migration, Permeability, DNA synthesis, Survival
LymphangiogenesisAngiogenesis
Bevacizumab CDP 791 PEG
Fab’ Fab’
-80
-60
-40
-20
0
20
40
60
80
-5 0 5 10 15 20
Scan day (relative to dosing)
% c
hang
e in
Ktr
ans
- - - repeatability (95 % CI on individual change)
EFFECT OF CDP791 ON ktrans
CDP-791 IS A BIOLOGICALLY ACTIVE KDR ANTAGONISTTon, Clin Cancer Res (In Press)
Dose related HTDisease stabilisation
⇒ CDP791 inactivates KDR in humans
KDR p-KDRCDP-791
-60
-40
-20
0
20
40
60
80
100
120
0.0 5.0 10.0 15.0 20.0 25.0 30.0 35.0
Dose (mg/kg)
Perc
ent c
hang
e in
who
le tu
mou
r vol
ume)
DOSE-LEVEL RELATED INHIBITION OF 3D TUMOR GROWTH
SUMMARY
DCE-MRIEvaluated in several phase I/II trials of VEGF inhibitorsΔDCE-MRI α DoseΔDCE-MRI α Disease StabilisationHeterogeneity is clinically significantPure KDR antagonists might not impact on tumour permeabilityPhase III evaluationVolumetrics
Who?Schedule? How Long?
ACKNOWLEDGEMENTS
Clinical MRIChan Ton Alan JacksonSaifee Mullamitha Geoff ParkerLynn Hope Caleb RobertsFiona Power Gio BuenoccorsiAndrew Clamp James O’ConnorSin LauJuan Valle UCB-CelltechMark Saunders Rob FelixGenny Connolly