Principles of translational medicine: imaging, biomarker imaging, theranostics Compiled by: Endre Mikus PhD, CEO Budapest, 21/9/2015
Imaging and imaging biomarkers An imaging biomarker is an anatomic, physiologic or molecular measurement obtained from an image that yields information about biological processes 2
The role of translational research in bioimaging 3 http://wwwsbica-staredusg/about/introductionphp
How the animal models could approach to the human pathology? Animal models Imaging Human Pathology Pharmacology model development 4
Rodent colonoscopy Analogue with human biomarker Biopsy option Do not need to exterminate the animals; model progression 5
Laser-Scanning in vivo confocal microscopy of the cornea Live (in vivo) histological cross-section representation of a normal cornea by IVCM 6
In vivo photoacoustic microscopy http://vimeocom/57851198#t=80 7 http://bmevirginiaedu/hu/
In vivo photoacoustic microscopy Anatomy Label-free photoacoustic microscopy images the concentration of hemoglobin and reveals the vascular anatomy down to single capillaries The close-up image shows a densely packed capillary bed and individual red blood cells traveling along a capillary 8 http://bmevirginiaedu/hu/
In vivo photoacoustic microscopy Function Spectroscopic photoacoustic microscopy images blood oxygenation (so2) in a human finger cuticle in vivo The so2 map of a capillary loop indicates that most oxygen is unloaded from hemoglobin at the tip of the loop 9 http://bmevirginiaedu/hu/
In vivo photoacoustic microscopy Molecular biomarker Molecular photoacoustic microscopy images Congo Red-labeled cerebral amyloid plaques in an Alzheimer s disease mouse 10 http://bmevirginiaedu/hu/
Magnetic Resonance Imaging (MRI) for mice Magnetic resonance imaging is a radiological tool used in the diagnosis of internal diseases in soft tissue, such as the brain and heart The 7-T, 40-cm MRI used to image multiple mice 11 http://wwwmouseimagingca/technologies/mrihtml
Micro-Computed Tomography (micro-ct) for mice High-resolution X-ray computed tomography produces detailed three-dimensional images of soft tissue and bone structure In the case of soft tissue, the highest resolutions are achieved with the help of a contrast agent, which increases the X-ray attenuation of the tissue of interest bone-metastases Liver of mice vasculature 12 http://wwwmouseimagingca/technologies/microcthtml http://openinlmnihgov/detailedresultphp?img=3095598_pone0019389g004&req=4
Positron emission tomography (PET-CT) for mice The primary use for the PET-CT system is in the development and validation of novel radiolabeled positron-emitting ligands, which can be used for tumor detection, diagnosis of cardiovascular and autoimmune disease or for establishing metabolic pathways Spatial resolution of 15 micron isotropic voxels, and can scan an entire mouse in less than 1 minute 13 https://csbmghharvardedu/mouse_imaging/pet-ct
Single photon emission computed tomography - computed tomography (SPECT-CT) imaging for mice The primary use of the facility is for the development and validation of novel radiolabeled imaging ligands which can be used for tumor detection, cell tracking, diagnosis of autoimmune diseases or vulnerable plaque localization The system can be used with various isotopes, most frequently 111In and 99mTc The spatial resolution for the SPECT system is approximately 1 mm 14 https://csbmghharvardedu/mouse_imaging/spect-ct
Target specific imaging 15
We need words BIOMARKERS Biomarkers are the words used by Translational research 16 http://sciclipswordpresscom/2012/01/09/cancer-theranostics-potential-applications-of-cancer-biomarker-database/
17 https://enwikipediaorg/wiki/file:molecularimagingtherapyjpg
The role of translational research in bioimaging 18 http://wwwradpittedu/?research/molecular-imaginghtml
GRP Receptor-Targeted PET chelate linker GPCR ligand Pancreas Carcinoma Xenograft in Nude Mice with a 68Ga-Labeled Bombesin(6 14) Analog 19 http://jnmsnmjournalsorg/content/46/4/691/f1expansion
GRP Receptor-Targeted PET CXCR4 expression was found in various human cancer types Development of specific tracers of CXCR4 for PET, will allow noninvasive evaluation of the receptor levels in vivo before and after chemotherapies or future anti-cxcr4 therapies 20 http://wwwthnoorg/v01p0251pdf
Theranostic Theranostics (or theragnostics) is portmanteau of Therapeutics and Diagnostics It refers to molecular/macromolecular targeting vectors and nano-platform technologies that incorporate both diagnostic and therapeutic functionalities 21
Nanoplex A therapeutic nanoplex containing multimodal imaging reporters was targeted to prostate-specific membrane antigen (PSMA), which is expressed on the cell surface of castrate-resistant PCa The nanoplex was designed to deliver small interfering RNA (sirna) along with a prodrug enzyme to PSMA-expressing tumors Downregulation of the selected sirna target, choline kinase (Chk), and the conversion of the nontoxic prodrug 5-fluorocytosine (5-FC) to cytotoxic 5-fluorouracil (5-FU) were also demonstrated with noninvasive imaging 22 http://nextbigfuturecom/2012/08/theranostic-imaging-offers-means-ofhtml
Expected pharmacology model Animal models Human Pathology Imaging Biomarker imaging Biomarkers Omics Theranostics 23
New paradigm in pharmacology (preclinical and clinical) 24 Researchers have to nominate targets which play fundamental pathological role in human disorders Nominate patient subpopulation (patient stratification) Determines biomarkers to follow the progression of the disease and/or check the efficacy of therapeutic intervention Pharmacologists have to find/develop the appropriate animal model (or create GMO animals) in which the human pathological pathway is exists and results disease phenotype Compound is in the right time in the right place and has the possibility to evoke therapeutic potencial The animal model do not need to show necessarly the same disease phenotype than that of human disease Detailed economic calculation on reimbursment and payback strategies
New paradigm in pharmacology The new pharmacology paradigm needs a closer collaboration among clinicians, translational research specialist and pharmacologist At the time of the start of drug discovery process the team must know the targeted patient subpopulation and has to have a solid clinical trial plan with biomarker options The same biomarkers are also expected to use in in vivo pharmacology models in order to translate the preclinical result to the clinic 25
Ortolog differences FACTORS HUMAN EXPERIMENTAL ANIMAL Genetic background Environment Heterogeneous, outbred, races Diverse, full of stress, pollutions, seasons etc Homogeneous, inbred, strains Well balanced, no stress, cleaned air, standard temperature and humidity, specific pathogen free conditions Food and beverages Different, complex Rodent chow, cleaned water Age, scenescence Wide range Usualy young Sex Both One of them prefered Chronic disease progression Generaly low Accelerated Disease phenotype Diverse Homogeneous Origin of the disease Natural Arteficial Anatomy/physiology Human Rodent 26 Placebo/nocebo effect Significant Missing
Thank you for your attention! 27