Principles of translational
medicine: imaging, biomarker
imaging, theranostics
Compiled by: Endre Mikus PhD, CEO
Budapest, 21/9/2015
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Imaging and imaging biomarkers
„An imaging biomarker is an anatomic,
physiologic or molecular measurement
obtained from an image that yields
information about biological processes”
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The role of translational research in
bioimaging
http://www.sbic.a-star.edu.sg/about/introduction.php
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How the animal models could approach
to the human pathology?
Animal
models
Human
Pathology
Pharmacology model
development
Imaging
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Rodent colonoscopy
Analogue with human biomarker
Biopsy option
Do not need to exterminate the animals; model progression
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Laser-Scanning in vivo confocal
microscopy of the cornea
Live (in vivo) histological cross-section
representation of a normal cornea by IVCM.
. 7 http://bme.virginia.edu/hu/
In vivo photoacoustic microscopy
http://vimeo.com/57851198#t=80
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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.
http://bme.virginia.edu/hu/
In vivo photoacoustic microscopy
Anatomy
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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.
In vivo photoacoustic microscopy
Function
http://bme.virginia.edu/hu/
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Molecular photoacoustic microscopy images Congo Red-labeled
cerebral amyloid plaques in an Alzheimer’s disease mouse.
In vivo photoacoustic microscopy
Molecular biomarker
http://bme.virginia.edu/hu/
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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.
http://www.mouseimaging.ca/technologies/mri.html
The 7-T, 40-cm MRI used to image multiple mice.
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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
Liver of mice vasculature
http://www.mouseimaging.ca/technologies/microct.html http://openi.nlm.nih.gov/detailedresult.php?img=3095598_pone.0019389.g004&req=4
bone-metastases
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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.
https://csb.mgh.harvard.edu/mouse_imaging/pet-ct
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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.
https://csb.mgh.harvard.edu/mouse_imaging/spect-ct
The system can be used with various isotopes, most
frequently 111In and 99mTc. The spatial resolution for the
SPECT system is approximately 1 mm.
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Target specific imaging
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BIOMARKERS
We need words
http://sciclips.wordpress.com/2012/01/09/cancer-theranostics-potential-applications-of-cancer-biomarker-database/
Biomarkers are the words
used by Translational
research
. 17 https://en.wikipedia.org/wiki/File:MolecularImagingTherapy.jpg
. 18 http://www.rad.pitt.edu/?research/molecular-imaging.html
The role of translational research in
bioimaging
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Pancreas Carcinoma Xenograft in Nude Mice with a 68Ga-Labeled
Bombesin(6–14) Analog
GRP Receptor-Targeted PET
http://jnm.snmjournals.org/content/46/4/691/F1.expansion
chelate
linker GPCR ligand
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CXCR4 expression was found in various human cancer types
Development of specific tracers of CXCR4 for PET, will allow non-
invasive evaluation of the receptor levels in vivo before and after
chemotherapies or future anti-CXCR4 therapies.
http://www.thno.org/v01p0251.pdf
GRP Receptor-Targeted PET
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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.
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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. Down-
regulation 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.
http://nextbigfuture.com/2012/08/theranostic-imaging-offers-means-of.html
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Expected pharmacology model
Animal
models
Human
Pathology
Imaging
Biomarker imaging
Biomarkers
Omics
Theranostics
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New paradigm in pharmacology
(preclinical and clinical)
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
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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.
New paradigm in pharmacology
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FACTORS HUMAN EXPERIMENTAL ANIMAL
Genetic background Heterogeneous, outbred,
races
Homogeneous, inbred, strains
Environment Diverse, full of stress,
pollutions, seasons etc.
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
Placebo/nocebo effect Significant Missing
Ortolog differences
Thank you for your attention!
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