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Ähnlich wie Non-invasive small animal imaging reveals antitumor and antimetastatic effects of PF-03732010 in preclinical cancer models
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Non-invasive small animal imaging reveals antitumor and antimetastatic effects of PF-03732010 in preclinical cancer models
- 1. Non-invasive small animal imaging in cancer drug research and development Cathy Zhang, Translational Research Group, Oncology Research Unit, Pfizer Global Research and Development, La Jolla Laboratories
- 2. Preclinical imaging modalities overview Clinical Modalities Light Output Application Characteristics Imaging anatomical, high throughput, low cost BLI luciferase labeled cells functional, high sensitivity/ No Bioluminescence /luciferin injection molecular low resolution fluorescence labeled anatomical, high sensitivity Fluorescence molecules or cells functional, Limited (exogenous/intrinsic) molecular (low cost) 18FLT-PET injection of 3’-Fluoro-3’ anatomical, high resolution Yes deoxythymidine functional (high cost) interaction of sound anatomical, high resolution Yes Ultrasound waves with living tissues functional (vasculature) anatomical, high resolution Yes CT n/a functional (bone, lung) Target – P-cadherin, CDK4 and Chk1
- 3. P-Cadherin target key profile Cell 1 Cell 2 Intracellular Plasma Space Cell surface glycoprotein /involved Membrane in Ca++-dependent cell-cell adhesion. actin Cadherin cytoskeleton Signalling is mediated by β- Dimers catenin nucleus In the cytoplasm, β-catenin is Adherens stabilized by Wnt signaling and Β-catenin/Tcf Junction translocates to the nucleus Wnt Target gene transcription In the nucleus, β-catenin/partners w/ Tcf factor to regulate Cytoplasm expression of oncogenes such as, c-myc, survivn, and cyclin D1 etc. tissue cell integrity Proliferation cell invasion
- 4. Disease progression in MDA-MB-435-HAL SRC model Fluorescence Bioluminescence day 33 IVIS200 (Caliper) ProSense Injection FMT (VisEn) Normal Lung 14 28 36 55 Days Post Tumor Implant 16 BLI (photons/sec x 108) 100 100 % of Survival 12 Percent survival SRC Model 75 Primary Tumor Mouse 75 Growth Survival Tumor Burden 8 50 in Lungs 50 4 25 25 0 0 0 0 25 50 75 100 0 25 50 75 Days Post Tumor Implant 100 Primary tumor and lung metastasis can be longitudinally tracked via BLI and FLI
- 5. PF-03732010 displays antitumor and antimetastatic property MDA-MB-435HAL-CDH3-SRC PC3M-CDH3 Lymph Node Metastasis Dorsal Vehicle Primary Vehicle PF-2010 Tumor (20 mg/kg) PF-03732010 20 mg/kg Ventral CTC (hAlu) PF-03732010 (mg/kg) 20 H&E 5 Staining 1 0 50 100 150 200 % of Control PF-03732010 induces antitumor and antimetastasis property in multiple models
- 6. Tumor growth inhibition of PF-03732010 in SC and SRC Model MDA-MB-435HAL-CDH3 16 1000 Control BLI x 108 (photons/sec) PF2010, 20mg/kg 120 Tunor volume (mm3) Vehicle 12 PF-2010, 40 mg/kg 800 Relative Tumor Size PF-2010, 20 mg/kg 90 (% of Control) PF-2010, 10 mg/kg 600 SC 8 SRC 60 implant implant 400 30 4 0 200 SRC SC Vehicle PF3732010 0 10 20 30 40 50 60 10 20 30 40 50 60 Days Post Tumor Implant Days post tumor implant PF-03732010 displays better efficacy in the MDA-MB-435HAL-CDH3 SRC model than SC model
- 7. Fluorescence imaging detect the IgG (PF-03732010) distribution 10 IgG Distribution M1 M2 M3 (x 10 photons/sec) 8 24 hr 1 hr Intensity 6 72 hr 4 9 24 hr 2 SRC tumor 0 sc tumor y ng n or nt r or ve ne SR Ski .I m m Lu Li id Sm Tu Tu 72 hr K SC C Serum concentration, nM 1000 IVIS200 (Caliper) T1/2 = ~ 7 days CL = 0.01ml/min/kg Vss = 0.18 L/kg Tumor implanted in sc (right flank) and 100 subrenal capsule (left side) SC injection with P-Cad IgG 10 mg/kg IV Drug level reached Cmax in 24 hr 10 10 mg/kg s.c. IgG distributes to sc and SRC location 0 168 336 504 672 Time, hr
- 8. PD modulation with the treatment of P-Cadherin IgG β-Catenin Merged Caspase 3 Ki67 IHC – Vehicle β-Catenin change - target modulation PF-2010 Increased apoptosis & 20 mg/kg decreased proliferation 18FLT-PET [18F]FLT-PET/CT CT Imaging [18F]FLT-PET Imaging Vehicle Vehicle Vehicle Suppression of [18F]FLT uptake kidney tumor PF-2010 PF-2010 PF-2010 Tumor in SRC Tumor in Lung Day 42
- 9. ATTENTION! The entire presentation is available to registered attendees only! To view the rest of this exciting presentation and many more! Please Register for the 7th Annual Cancer Drugs Research and Development Conference at www.gtcbio.com If you are already registered, please contact GTCbio for the full version.