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