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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