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Molecular Markers for medical imaging and therapy Provisional schedule Assessment : bibliographic report Some biological molecules associated to cancer physiology The molecular marker market and companies Lectures in « molecular markers for medical imaging and therapy» Oct 2, 13h30-15h30, M-256 Jean-Claude VIAL, Directeur de recherche (CNRS), Lab. Spectrométrie Physique Probes for optical microscopy Oct 16, 13h30-15h30, M-256 Chantal REMY, Directrice de recherche (INSERM), Lab. Neuro-imagerie Fonctionnelle et Métabolique -Institut des Neurosciences MRI for anatomical, functional and molecular imaging Nov 20 13h30-15h30, M-255 Laurent Riou, Chargé de Recherche (INSERM), Faculté de Médecine, Development of markers for molecular imaging : application to cardiology Jan 25, 14h-17h Thierry Bettinger, research scientist Bracco Research SA, Ultrasound contrast agents and ultrasound-mediated delivery Jan 18 13h30-15h30 Jean-Luc COLL, Directeur de recherche (INSERM), Institut Albert Bonniot, Vectorisation of large molecules for biotherapy of cancer Géraldine Le Duc ESRF, ligne médicale ID17 - Grenoble, FR Contrast agents for Xray imaging and radiotherapy Jean-Marc DINTEN, Lab. Imagerie et Systèmes d'Acquisition –Léti - Fluoptics Fluorescence intraoperative readers and dedicated fluorescence markers Lecturers in « molecular markers for medical imaging and therapy» Grenoble Institute or Neurosciences ESRF Laurent Riou Géraldine Le Duc Chantal REMY CEA-LETI/DTBS Albert Bonniot Institute Jean-Marc DINTEN Jean-Luc COLL Fluoptics LiPhy Bracco Jean-Claude VIAL Thierry Bettinger « Molecular markers for medical imaging and therapy» assessment Each lecturer will propose a subject and some bibliography Choose one of them Write down a short report (4-6 pages) Send it to the teacher who proposed the subject and myself ([email protected]) Deadline : February 28 Important notice : The report should be written in english Use the information from other courses : MRI, MAR, IP, cell signaling or physiology This should be your own work : don’t “copy-paste” sections of articles or other’s work available on internet When you use an image from internet, give the reference and the name of the author Molecular Markers for medical imaging and therapy Provisional schedule Assessment : bibliographic report Some biological molecules associated to cancer physiology The molecular marker market and companies Steps in cancer development http://scienceeducation.nih.gov/supplements/nih1/cancer/guide /understanding1.htm Initiation Multiple mutations (< 10) in : - tumor suppressor genes, oncogenes cell signaling - DNA repair mechanisms Tumor development Clonal selection of cells with - impaired cell cycle regulation faster division rate - ability to attract blood vessels angiogenesis - reduced susceptibility to Natural Killer cells survival Metastasis Clonal selection of cells with - reduced adhesion ‘endothelial to mesenchymal transition’ - increased motility invasive cells - colonization of lymph nodes, then other tissues Developmental and tumoral angiogenesis VEGF induces the differentiation and proliferation of endothelial cells Angiopoietin-1 (Ang-1) induces vascular developmement Angiopoietin-2 (Ang-2) induces vascular destabilization http://www.unifr.ch/pathology/en/background/tumorangiogenesis Cell adhesion molecules (receptors) N-CAM, I-CAM (neural cell, intercellular adhesion molecules) : adhesion molecules containing IgG domains Cadherins (about 20 members, among them E-, N-, P-cadherins) : calcium dependent adhesion Selectins (E-, L-, P-selectins) : adhesion molecules recognizing sugar polymers Integrins (about 24 members) : cell surface receptors recognizing various extracellular matrix molecules or cell surface proteins The EPR effect (Enhanced Permeability and Retention Effect) Rapidly growing new blood vessels are leaky enhanced permeability Tumor cells often have intense endocytic and phagocytic activity enhanced retention As a result, actively growing tumors take up more molecular markers than the rest of the tissue Duncan et al, Nat Reviews in Discovery 2, 347-360, 2003 Molecular Markers for medical imaging and therapy Provisional schedule Assessment : bibliographic report Some biological molecules associated to cancer physiology The molecular marker market and companies Drug discovery and development Critical steps : proof of concept (usually in small animals) Toxicity study in animals, lethal dose, biodistribution Phase 1 : toxicity in humans, side effects ?, double-blind study using placebo as a control Phase 2 : proof of effect in humans (100 persons), determination of useful dosage, double-blind study using the best therapeutic treatment as a control Phase 3 : large scale study (> 1000 persons), side-effects Applications of imaging during drug discovery and development Imaging-based biomarkers have many uses in all phases of the drug development process They can aid in target discovery and validation and characterize drug-target interaction and modulation. Imaging end points can minimize time-intensive histologic analyses in both preclinical and clinical testing. As disease biomarkers, imaging end points can help define, stratify, and enrich clinical study groups. In addition to facilitating early clinical pharmacokinetic/pharmacodynamic assessments, imaging-based biomarkers can also serve as early surrogates of therapy success. GaryJ. Kelloff Clin Cancer Res 2005; 11: 7967. Molecular markers today Example of GE Healthcare Molecular markers are used to : - increase image contrast - in vivo diagnostic - monitor drug distribution - monitor drug effects Molecular markers tomorrow http://www.targeson.com/ Ultrasound imaging http://www.braccoimaging.com/ http://www.fluoptics.com/ Infrared fluorescence imaging Integrin structure and families 18 a chains 8 b chains 24 ab pairs inactive active Example of ‘RGD’ containing protein : fibronectin, vitronectin http://www.unifr.ch/pathology/en/background/tumorangiogenesis Integrin signaling Outside-in and inside-out signaling http://www.unifr.ch/pathology/en/background/tumorangiogenesis The complex structure of growing tumors