IMAGING ANGIOGENESIS. Gordon Jayson Manchester UK

Transcription

1 IMAGING ANGIOGENESIS Gordon Jayson Manchester UK

2 REGULATION OF ANGIOGENESIS Angiogenic factors Anti-Angiogenic proteins Cytokines VEGF FGF HGF HB-EGF Angiogenin IL-8 PDGF Enzymes TP Protein fragments endostatin angiostatin Inhibitory proteins PF4 Soluble receptors s-flt s-fgf R

3 VEGFi INCREASE RR, PFS +/-OS IN SOLID TUMOURS Renal Yang NEJM 23 Lung Sandler NEJM 26 CRC Hurwitz NEJM 24 Breast Miller ECCO 25 Who? Schedule? How Long? Liver Llovet, ASCO 27

4 NEW AND FUTURE TARGETS Integrins PDGF: CP-868,596 Lewis, ASCO 27 Sarcoma, Spindle Cell, NSCLC vascularised volume (ml) total tumour volume (ml) Jayson JCO 25 CNTO 95 Mullamitha, Clin Cancer Res 27 Cilengitide Reardon, ASCO 27

5 NEW AND FUTURE TARGETS Integrins PDGF: CP-868,596 Lewis, ASCO 27 Ang: AMG 386 (Ang 1, 2) Rosen ASCO 27 Ovarian HGF: ARQ 197 (c-met RTKi) Garcia ASCO 27 XL88 (c-met, VEGFR2 RTKi) Eder ASCO 27 Prostate, NET, Testicular VDAs CT Combretastatin Metronomic CNTO 95 Mullamitha, Clin Cancer Res 27 Cilengitide Reardon, ASCO 27 DLL4 Neuropilin FGFs Ridgeway, Nature 26

6 ANTI-VASCULAR COMBINATION REGIMENS Docetaxel, AEE778 HeyA8 cell line VEGF, Cytotoxic Kamat et al., Cancer Res 27 PBS MTD CT MET CT MTD CT MET CT VEGF RTKi VEGF RTKi VEGF RTKi VEGF, DLL4 Ridgeway, Nature 26 VEGF, FGF Casanovas Cancer Cell 25

7 IMAGING THE VASCULATURE Signal (T1) MITR Max. gradient Time to 9% max Amplitude VEGF - VEGF + Time (s) K trans Endothelial permeability surface area product

8 PHARMACODYNAMIC/ BIOMARKER IMAGING OF ANGIOGENESIS Jayson JNCI mg/kg % max. permeability mg/kg Day Day 2 Day 35

9 PROOF THAT VEGF IS INHIBITED IN PATIENTS Wedam JCO 26 BL-C1 BL-C4/7 Ki MVD VEGF-A pvegfr pvegfr VEGFR TUNEL BL-C1 BL-C4 BL-C7 Ktrans Kep Ve

10 Flow Volume Permeability ANTI-VEGF Ab INHIBIT THE VASCULATURE Willett Nat Med 24 Bevacizumab 5mg/kg Days and 12 MVD Pericytes IFP FDG-PET CEPs CECs

11 Δ DCE-MRI PROPORTIONAL TO DOSE OF VEGFi 6 4 AZD2171 Drevs (ASCO 27) % change IAUC AUC (ng.h/ml) AG Liu (JCO 25) BIBF112 Mross ASCO 25, PTK/ZK Morgan JCO 23 Thomas JCO 25 Change in K trans (%) AG Plasma 24 hours AUC (ng.h/ml)

12 Δ DCE-MRI IS RELATED TO OUTCOME 1 PTK/ZK Morgan JCO 23 Thomas JCO 25 Tumor Size Change by Day 56 (%) Baseline MRI ki (day 2: %) Reductions of >5% K trans are associated with stabilization Relationship between K trans and PFS reported with Sorafenib in renal cancer (O Dwyer ASCO 25)

13 VASCULAR HETEROGENEITY Jayson, JNCI, PET PK days Tumor Tumor liver spleen r.kidney l.kidney aorta f.arteries lung thyroid brain Tumor Tumor Tumor Tumor Tumor Tumor -25-5

14 Anti-VEGF Ab AIF Parameter Model ROI Stats HuMV833Jayson 22 Manual K trans, Kfp, V p Tofts, ET Entire tumor Mean +/-SD BevacizumabOvermoyer 24 K ep BevacizumabDoshi 25 K trans, K p, V e, IAUGC Brix, Kety Enhancing reg Base, single Δ BevacizumabWedam 26 K trans, K ep, V e Brix VEGF R AZD2171Drevs 25 IAUGC Decrease CDP791Jayson 26 Standard K trans, V p, V e, flow Entire tumor VTV, IAUGC VEGFR/PDGFR TKi SU5416Medved 24 Not required IAUGC, washout, Heuristic ΔMean SU5416O Donnell 25 Cmax, K trans, V e NS Pixel based Median PTK/ZK Morgan 23 Standard K i Larsson Section Δbaseline PTK/ZK Yung 23 K i, CBV NS ΔMean PTK/ZK Mross 25 Standard K i Larsson Entire tumor Δbaseline PTK/ZK Thomas 25 K i Larsson Entire tumor ΔMean AG13736Liu 25 Rijpkema K trans, IAUGC Tofts, Heur Entire tumor ΔMean BAY 43-96O Dwyer 25 Manual K trans Tofts Δbaseline VEGFR/PDGFR/FGFR TKi SU6668Xiong 24 IAUGC, slope Heuristic CT Δbaseline BIBF112Mross 25 K trans, IAUGC Δbaseline Anti-PDGFRβ CDP86Jayson 25 Standard K trans, V e, V p, flow, Tofts, ET, Entire tumor Median, mean VTV, IAUGC LL Heur Anti-Integrin CNTO95Jayson 25 Standard K trans, V e, V p, flow, Tofts, ET Entire tumor Median, mean VTV, IAUGC LL, Heur EndostatinEder 22 Manual K trans, V e Tofts Entire tumor

15 STATISTICAL ANALYSIS OF DATA IS PROBLEMATIC Perfusion in pulmonary metastasis from renal cancer From Liu JCO 25

16 VASCULAR PARAMETERS, HETEROGENEITY AND PROGRESSION.25 * # * Progressive Stable/better Progressive Stable/better More IAUC (mmol.min) more Ve normalised frequancy normalised frequancy Ve * * # # p.1 Progressive p.5 Stable/better # p.1 * p Progressive Stable/better more K Ktrans (/min) More Vp relative frequency normalised frequancy

17 BASELINE ENHANCING FRACTION PREDICTS OUTCOME IN OVARIAN CANCER O Connor, Clin Cancer Res (In press)

18 [ 18 F]-FLT: BIOMARKER FOR BEVACIZUMAB IN GLIOMA Chen, JCO 27

19 INTERSTITIAL PRESSURE Willett, Nat Med 24 NORMALISATION Winkler, Cancer Cell, 24 VASCULAR PERMEABILITY Jayson JNCI 22

20 THE VEGF FAMILY AND ITS RECEPTORS Fab Fab Bevacizumab CDP 791 PEG VEGF-A VEGF-B PlGF VEGFR-1 VEGF-A VEGF-C VEGFR-2 VEGF-C VEGF-D VEGFR-3 P P P P P P P P P P P P Migration, Permeability, DNA synthesis, Survival Angiogenesis Lymphangiogenesis

21 EFFECT OF CDP791 ON k trans repeatability (95 % CI on individual change) 4 % change in K trans Scan day (relative to dosing)

22 CDP-791 IS A BIOLOGICALLY ACTIVE KDR ANTAGONIST Ton, Clin Cancer Res (In Press) Dose related HT Disease stabilisation KDR CDP-791 p-kdr CDP791 inactivates KDR in humans

23 DOSE-LEVEL RELATED INHIBITION OF 3D TUMOR GROWTH 12 Percent change in whole tumour volume) Dose (mg/kg) -4-6

24 SUMMARY DCE-MRI Evaluated in several phase I/II trials of VEGF inhibitors ΔDCE-MRI α Dose ΔDCE-MRI α Disease Stabilisation Heterogeneity is clinically significant Pure KDR antagonists might not impact on tumour permeability Phase III evaluation Volumetrics Who? Schedule? How Long?

25 ACKNOWLEDGEMENTS Clinical Chan Ton Saifee Mullamitha Lynn Hope Fiona Power Andrew Clamp Sin Lau Juan Valle Mark Saunders Genny Connolly MRI Alan Jackson Geoff Parker Caleb Roberts Gio Buenoccorsi James O Connor UCB-Celltech Rob Felix