Molecular Markers for medical imaging and therapy

Report
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

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