Biological Imaging : Gene-Diagnosis-Therapy. M. Schwaiger * Technische Universität Munich Germany. European Commission 7th Framework

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1 Biological Imaging : Gene-Diagnosis-Therapy M. Schwaiger * Technische Universität Munich Germany European Commission 7th Framework Pa

2 Biological Imaging Hypotheses Research tool in basic and clinical sciences Allows sophisticated strategies for translational research Supports clinical research by providing surrogate endpoints Allows acceleration of new drug development

3 Why Multi-Modality Imaging? More than Molecular Imaging Definition of Tissue Structure and Anatomy Tissue Density, MR-Relaxation, Backscatter Measurement of Physiologic Function Blood Flow, Tissue/Organ Performance Quantitation of Protein Expression Receptor Ligands, Enzyme-Substrate Determination of Down Stream Effects Tracer Transport, Metabolism Assessment of Gene Expression Antisense and Reporter Gene Imaging

4 Biological Imaging Hypotheses Research tool in basic and clinical sciences Allows sophisticated strategies for translational research Supports clinical research by providing surrogate endpoints Allows acceleration of new drug development

5 Therapy Monitoring by Assessment of Tumor Metabolism Time course of therapy induced changes during CHOP therapy coronal 14 axial Tag Tag K [ml/100g/min] day 0 day 7 day 42 Non-Hodgkin lymphoma Römer et al. Blood 91: (1998)

6 FDG-PET in NHL after first line chemotherapy Progression free survival (%) (N = 67) p < (N = 26) 2 year PFS PET negative 85% PET positive 5% Spaepen, Stroobants et al. J Clin Oncol 2001, 19:

7 Anti-Angiogenic Therapy Inhibition of growth receptors VEGF receptor antagonists: SU5416, SU6668, PTk787 EGF receptor antagonists: ZD1839, IMC-C225 MMP inhibitors Marimastat, AG3340, Bay , BMS Endogenous inhibitors Endostatin, Angiostatin Integrin antagonists Vitaxin, EMD121974

8 Radiohalogenated Glycosylated RGD-Peptides OH * I HO HO AcHN SAA1 OH O O NH OH OH O SAA2 HO O NH H N 18 F O D-Tyr HN CO NH O Lys D-Phe HN CO NH O Lys Asp Arg Asp Arg Gly Gly [ * I]c(RGDyK(SAA1)) [*I]Gluco-RGD IC 50 (α V β 3 ) = 40 nm IC 50 (α V β 5 ) = 2,000 nm IC 50 (α IIb β 3 ) = 5,000 nm [ 18 F]c(RGDfK(SAA2)) [ 18 F]Galacto-RGD IC 50 (α V β 3 ) = 5 nm IC 50 (α V β 5 ) = 1,000 nm IC 50 (α IIb β 3 ) = 6,000 nm

9 Non invasive imaging of αvβ3-expression in humans soft-tissue sarcoma right knee immunohistochemistry blood vessel sagittal: Galacto-RGD-PET PET-CT Fusion αvβ3 staining melanoma: lymph node metastasis right axilla lymph node blood vessel axial: Galacto-RGD-PET PET-CT Fusion αvβ3 staining Beer et al., No. 547

10 In Vitro In Vivo histology CEA p53 PSA ERBB2/neu VEGF MYC Molecular Markers Contrast-Enhanced MRI Buzz word: Personalized Medicine Microarray Data CT

11 Recommendations for 7th Program Biological Imaging will be an important aspect of basic and clinical research and technology development should be founded (Nano,Optics,etc) Interdisciplinary Centers of Excellence should be supported (ie NIH program) Individual competitive research projects in this area should stimulate innovation

12 Interdisciplinary Centers For Biological Imaging Clinical Research Klinische Bildgebung PET/CT Radiopharmaka MR-PET Zyklotron Zyklotron Tracerentwicklung Pathologie Pathologie Basic Sciences Biotechnologie / Industrie Molekulares Bildgebungs-Zentrum der TUM Klinikum rechts der Isar Technische Universität München

13 PET Reporter Gene Imaging Reporter Gene Gene Product Reporter Probe Ligands FESP SST-Analogues Receptors D2R SSTR Transporters Na-I-S NET Iodine HED Substrates FIAU FHBG Enzymes HSV1-TK HSV1-sr39TK Vector Reporter Gene

14 Prognostische Bedeutung der FDG PET unter neoadjuvanter Therapie von Ösophaguskarzinomen Prognostische Bedeutung der Methylentetrahydro- folate-reduktase- Expression Überlebenswahrscheinlichkeit p = PET responder (n=15) Überlebenswahrscheinlichkeit p = High MTHFR (n=27) PET non-responder (n=22) Monate Low MTHFR (n=11) Monate nach Operation 80 Weber, Ott et al., J Clin Oncol, 2001; 19: Pathologie

15 Visualisation of Tumor Biology Receptors Transporters Peptide Receptors Nucleosides Acetate FDG Enzymes Enzymes Nucleosides Antibodies Integrins Choline O 2 Local Concentration Amino Acids Local Concentration

16 APX MID BASE Rat myoblast (wt) Rat myoblast (retro v. NIS) Rat myoblast (adeno v. NIS) Human endothelial progenitor cell (wt) Human endothelial progenitor cell (retro v. NIS)

17 Monitoring of high dose chemotherapy in lymphoma by FLT-PET FDG-PET/CT before CTx FLT-PET before CTx FLT-PET after 7 days of CTx SUV 7.8 SUV 8.5 SUV year old patient with high grade NHL, treated with CHOP

18 Zusammenfassung PET/CT wird sich als Standardverfahren in der Onkologie für Staging und Therapiekontrolle etablieren Molekulare Bildgebung muss sich klinisch bewähren; PET/CT erlaubt zeitnahe Evaluierung PET/CT in der Kardiologie hängt von dem Erfolg des Plaque Imaging ab PET/MR wird als nächste Geräte Kombination mit Schwerpunkt funktionelle Gewebecharakterisierung verwirklicht werden