Molecular Imaging
and
Genomics
Radiology Dept.,Ruijin Hospital
SSMU
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Molecular Imaging
Imageology
Radiology
Technology development to spearhead the
revolution in medicine….,
G e n o m i c s a n d M o l e c u l a r I m a g i n g
DNA/Protein
MicroArrays
Affymetrix
Integrated Diagnostics,
in Vivo Imaging tied
to Applied Genomics
Molecular Imaging Components
Source,
Uzgiris,GE CRD
Tjuvajev,Blasberg,
Larson,MSKCC
Drugs needing more specific disease
diagnosis or genetic data on patient
Chemistry libraries
Novel agents/tracers
Biochemistry
Pharmacology
MOLECULAR
IMAGING
Molecular
Biology
PET,MRI,MRSI
Core Technologies,
1.Hi Sens/Spec Imaging
2.Image Analysis
Imaging Physics,
Engineering
Integrating Critical Skills… Imaging with Diagnostics …
Diagnostics with Therapeutics
G e n o m i c s a n d M o l e c u l a r I m a g i n g
? Fundamental Technology
Hurdles
? Platform Concepts
? Disease Targets
? Industry and Academic
Partnerships
Project
Definition
Technology Focus Areas,
? MR and PET Diagnostic Agents
? Biomarker Discovery and Clinical IVD
? Biomedical Informatics and Computing
? Clinical Translation and Imaging Optimization
? Optical Imaging
Broad Based Technology Platform Approach
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Molecular Tools
Compartments
(Blood,Lipophilic Tissue (fat),
Metabolic Active (muscle),Elimination
(liver,kidney)…)
Physio-chemical
(Metabolism,Oxygenation,Diffusion,
pH,Transport Characteristics,
Elimination,Phagocytosis,Cell-type
Specific…)
Biological
(Cell Surface Receptors,Antigens,
Transporters,Gene Sequences,Proteins,
Enzymatic Activity,Post Translational
Modification…)
Anatomical
Molecular
Molecular Imaging,Pathology Specific Molecular Markers
Disease Specific Metrics
Vulnerable Plaque Imaging
G e n o m i c s a n d M o l e c u l a r I m a g i n g
CV,Myocardial Infarction
Societal Cost
6M emergency room visits/year (US); 2.5M admitted to critical care unit
34K sent home improperly
Genomic
? Lipoprotein A
(positive prognosis)
? C-reactive protein
(negative prognosis)
Symptomology
? Angina (chest pain)
? Standard blood gas,
electrolyte and blood
chemistry measures
IVD
? Platelet activation
and fibrinogen
metrics
? Suggest plaque
rupture,fissure and
thrombosis
Scan/DPharma
? Targeted SPECT
agent (apoptosis) and
cellular viability
measure
? Evaluation of
viable v necrotic v
pre-apoptotic heart
tissue and hemorrhage
potential
Therapy
? Thrombolytic
to restore
blood flow to
affected tissue
? Anti-
apoptotic agent
(caspase-3
inhibitor) to
allow pre-
apoptotic
recovery
Therapy Evaluation
N
N
NH
O
O
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Approach
? Basis of research focus and target selection
? Largest unmet clinical need
? Diagnostic affects therapy choice &
outcome
? Surrogate for disease modifying claims
? Diagnostic-therapeutic co-development
? Development of molecular imaging agent(s)
? Development of clinical IVD test
Comprehensive Molecular Diagnostics
Program in Cardiovascular Disease
Disease Focus
?Atherosclerosis
? Plaque burden
? Inflammatory component,thrombotic risk
? Endothelial dysfunction
?Ischemic heart disease
? Transient ischemia
? Ischemic footprint and progression
Targets
?Molecular Imaging Agents
?Oxidized lipoproteins and their receptors
?Targets in inflammatory cascade
?Apoptosis
?In Vitro Diagnostics
?Ischemia modified proteins
Platform Technologies
?Molecular Imaging Agent
?Reptating polypeptide (MRI)
?Iron oxide nanoparticles (MRI)
?F-18 labeled peptides (PET)
?Engineered antibody targeting (PET)
?Pathway informatics tool
N or m al
F at t y
S t r ea k
V u l n er ab le
P laq u e
O c c l u s i v e
A S P laq u e
R u p t ur e/
T h r om bo s i s
C l i n i c a l l y S i l e n t S t r e s s t e s t
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Approach and opportunity
? Opportunity,disease modifying therapy
pipeline
? Early differential diagnosis
? Diagnosis to affect therapy choice &
outcome
? Surrogate for disease modifying claims
? Diagnostic-therapeutic co-development
? Application of high field (3T) MRI
? Development of molecular imaging agent(s)
? Disease pathogenesis & molecular
mechanisms
CNS Disease,Comprehensive Imaging Program
Expanding to Diagnostic Agents
Disease Focus
? Alzheimer’s disease and other dementia
? Ab processing,aggregation,and
clearance
? Brain iron metabolism and overload
? Inflammation and the role of microglia
? Multiple Sclerosis
? Autoimmune response and inflammation
Targets
?Molecular Imaging Agents – ‘03
? Ab and NFT burden
? Targets in inflammatory cascade
? Apoptosis
?Molecular Mechanisms
? Role of metals in neurotoxicity
? Model of brain iron metabolism
Platform Technologies
?3T MR Imaging
? Structural MRI
? Brain iron imaging
? Proton Spectroscopy
?Platform Technologies
? Brain tissue analysis,histology,ex
vivo imaging
? Quantitative MRI
?Computer-aided prognostics
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Long and Narrow Linear Molecules Could
Penetrate Tumor Endothelium
i n t e r s t i t i u m
m a t r i x
e n d o t h e l i u m
l u m e n
A g e n t E n d o t h e l i u m P e n e t r a t i o n
c o i l e d m o l e c u l e
s m a l l m o l e c u l e
l i n e a r m o l e c u l e
P a ra m a g n e t i c i o n,G d
C h e l a t o r,D T P A
B a c k b o n e p o l y m e r,
p o l y l y s i n e p e p t i d e
A g e n t Sy n t h e si s
Conceptual Illustration
A Novel MR Agent for Tumor Angiogenesis Evaluation
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Rat Mammary Adenocarcinoma in Female Fisher
Rats 24 hours After Agent Injection
Rat #1 with Tumor
Linear polymer,0.025 mmol Gd/kg
Rat #2 with Tumor
Linear Polymer,0.025 mmol Gd/kg
Control
Coiled Polymer,0.025 mmol Gd/kg
Tumor Contrast Depends on the Conformation of the Agent
A Novel MR Agent for Tumor Angiogenesis Evaluation
G e n o m i c s a n d M o l e c u l a r I m a g i n g
G e n o m i c s a n d M o l e c u l a r I m a g i n g
3.0 T Images Highlighting Pixels with Low Values of Effective T2
Volunteer
Dementia Patient
Thin-slice,T2-weighted coronal images
demonstrate increased distribution of
pixels with short effective T2 (here
less than 46 msec) in brain of
dementia patient as compared to
normal volunteer,
To validate potential of brain iron of
biomarker for AD or other NDDs it is
necessary to,
? verify iron as causative factor in
producing the low T2 pixels (cadaver
brain studies),
? collect 3T MR data on patients and
age-matched controls,
? develop image post-processing
techniques to quantify anatomical
and statistical characteristics of low
T2 pixels,
G e n o m i c s a n d M o l e c u l a r I m a g i n g
High Resolution
2 D Multi-Element Image
Brain Tissue Characterization,Identify Biomarkers and
Develop Insights into Disease Pathology
High Resolution
Optical Photography High Resolution
Micro-MR Image* *Imaging generously provided by Al Johnson’s Group at Duke University on 7T Instrument
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Bioinformatics,Pathway Elucidation
Combination of Wet (Experiments) and Dry (Informatics) leading to
? discovery of biomarkers for in-vitro diagnostics
? discovery and optimization of targets for molecular imaging
Pathway Database
Analysis Engine Simulation Engine
Natural Language Database Wrappers
Internal/Proprietary Data
Wet Lab
Experiments
Summarized Mined Data
Testable Hypothesis
Pathway Informatics Platform
Viewable Pathway Maps Public Data
,G e n o m i c s a n d
M o l e c u l a r I m a g i n g,,,
T h e f u t u r e o f I m a g i n g,,,
T h e f u t u r e o f M e d i c i n e,
and
Genomics
Radiology Dept.,Ruijin Hospital
SSMU
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Molecular Imaging
Imageology
Radiology
Technology development to spearhead the
revolution in medicine….,
G e n o m i c s a n d M o l e c u l a r I m a g i n g
DNA/Protein
MicroArrays
Affymetrix
Integrated Diagnostics,
in Vivo Imaging tied
to Applied Genomics
Molecular Imaging Components
Source,
Uzgiris,GE CRD
Tjuvajev,Blasberg,
Larson,MSKCC
Drugs needing more specific disease
diagnosis or genetic data on patient
Chemistry libraries
Novel agents/tracers
Biochemistry
Pharmacology
MOLECULAR
IMAGING
Molecular
Biology
PET,MRI,MRSI
Core Technologies,
1.Hi Sens/Spec Imaging
2.Image Analysis
Imaging Physics,
Engineering
Integrating Critical Skills… Imaging with Diagnostics …
Diagnostics with Therapeutics
G e n o m i c s a n d M o l e c u l a r I m a g i n g
? Fundamental Technology
Hurdles
? Platform Concepts
? Disease Targets
? Industry and Academic
Partnerships
Project
Definition
Technology Focus Areas,
? MR and PET Diagnostic Agents
? Biomarker Discovery and Clinical IVD
? Biomedical Informatics and Computing
? Clinical Translation and Imaging Optimization
? Optical Imaging
Broad Based Technology Platform Approach
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Molecular Tools
Compartments
(Blood,Lipophilic Tissue (fat),
Metabolic Active (muscle),Elimination
(liver,kidney)…)
Physio-chemical
(Metabolism,Oxygenation,Diffusion,
pH,Transport Characteristics,
Elimination,Phagocytosis,Cell-type
Specific…)
Biological
(Cell Surface Receptors,Antigens,
Transporters,Gene Sequences,Proteins,
Enzymatic Activity,Post Translational
Modification…)
Anatomical
Molecular
Molecular Imaging,Pathology Specific Molecular Markers
Disease Specific Metrics
Vulnerable Plaque Imaging
G e n o m i c s a n d M o l e c u l a r I m a g i n g
CV,Myocardial Infarction
Societal Cost
6M emergency room visits/year (US); 2.5M admitted to critical care unit
34K sent home improperly
Genomic
? Lipoprotein A
(positive prognosis)
? C-reactive protein
(negative prognosis)
Symptomology
? Angina (chest pain)
? Standard blood gas,
electrolyte and blood
chemistry measures
IVD
? Platelet activation
and fibrinogen
metrics
? Suggest plaque
rupture,fissure and
thrombosis
Scan/DPharma
? Targeted SPECT
agent (apoptosis) and
cellular viability
measure
? Evaluation of
viable v necrotic v
pre-apoptotic heart
tissue and hemorrhage
potential
Therapy
? Thrombolytic
to restore
blood flow to
affected tissue
? Anti-
apoptotic agent
(caspase-3
inhibitor) to
allow pre-
apoptotic
recovery
Therapy Evaluation
N
N
NH
O
O
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Approach
? Basis of research focus and target selection
? Largest unmet clinical need
? Diagnostic affects therapy choice &
outcome
? Surrogate for disease modifying claims
? Diagnostic-therapeutic co-development
? Development of molecular imaging agent(s)
? Development of clinical IVD test
Comprehensive Molecular Diagnostics
Program in Cardiovascular Disease
Disease Focus
?Atherosclerosis
? Plaque burden
? Inflammatory component,thrombotic risk
? Endothelial dysfunction
?Ischemic heart disease
? Transient ischemia
? Ischemic footprint and progression
Targets
?Molecular Imaging Agents
?Oxidized lipoproteins and their receptors
?Targets in inflammatory cascade
?Apoptosis
?In Vitro Diagnostics
?Ischemia modified proteins
Platform Technologies
?Molecular Imaging Agent
?Reptating polypeptide (MRI)
?Iron oxide nanoparticles (MRI)
?F-18 labeled peptides (PET)
?Engineered antibody targeting (PET)
?Pathway informatics tool
N or m al
F at t y
S t r ea k
V u l n er ab le
P laq u e
O c c l u s i v e
A S P laq u e
R u p t ur e/
T h r om bo s i s
C l i n i c a l l y S i l e n t S t r e s s t e s t
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Approach and opportunity
? Opportunity,disease modifying therapy
pipeline
? Early differential diagnosis
? Diagnosis to affect therapy choice &
outcome
? Surrogate for disease modifying claims
? Diagnostic-therapeutic co-development
? Application of high field (3T) MRI
? Development of molecular imaging agent(s)
? Disease pathogenesis & molecular
mechanisms
CNS Disease,Comprehensive Imaging Program
Expanding to Diagnostic Agents
Disease Focus
? Alzheimer’s disease and other dementia
? Ab processing,aggregation,and
clearance
? Brain iron metabolism and overload
? Inflammation and the role of microglia
? Multiple Sclerosis
? Autoimmune response and inflammation
Targets
?Molecular Imaging Agents – ‘03
? Ab and NFT burden
? Targets in inflammatory cascade
? Apoptosis
?Molecular Mechanisms
? Role of metals in neurotoxicity
? Model of brain iron metabolism
Platform Technologies
?3T MR Imaging
? Structural MRI
? Brain iron imaging
? Proton Spectroscopy
?Platform Technologies
? Brain tissue analysis,histology,ex
vivo imaging
? Quantitative MRI
?Computer-aided prognostics
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Long and Narrow Linear Molecules Could
Penetrate Tumor Endothelium
i n t e r s t i t i u m
m a t r i x
e n d o t h e l i u m
l u m e n
A g e n t E n d o t h e l i u m P e n e t r a t i o n
c o i l e d m o l e c u l e
s m a l l m o l e c u l e
l i n e a r m o l e c u l e
P a ra m a g n e t i c i o n,G d
C h e l a t o r,D T P A
B a c k b o n e p o l y m e r,
p o l y l y s i n e p e p t i d e
A g e n t Sy n t h e si s
Conceptual Illustration
A Novel MR Agent for Tumor Angiogenesis Evaluation
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Rat Mammary Adenocarcinoma in Female Fisher
Rats 24 hours After Agent Injection
Rat #1 with Tumor
Linear polymer,0.025 mmol Gd/kg
Rat #2 with Tumor
Linear Polymer,0.025 mmol Gd/kg
Control
Coiled Polymer,0.025 mmol Gd/kg
Tumor Contrast Depends on the Conformation of the Agent
A Novel MR Agent for Tumor Angiogenesis Evaluation
G e n o m i c s a n d M o l e c u l a r I m a g i n g
G e n o m i c s a n d M o l e c u l a r I m a g i n g
3.0 T Images Highlighting Pixels with Low Values of Effective T2
Volunteer
Dementia Patient
Thin-slice,T2-weighted coronal images
demonstrate increased distribution of
pixels with short effective T2 (here
less than 46 msec) in brain of
dementia patient as compared to
normal volunteer,
To validate potential of brain iron of
biomarker for AD or other NDDs it is
necessary to,
? verify iron as causative factor in
producing the low T2 pixels (cadaver
brain studies),
? collect 3T MR data on patients and
age-matched controls,
? develop image post-processing
techniques to quantify anatomical
and statistical characteristics of low
T2 pixels,
G e n o m i c s a n d M o l e c u l a r I m a g i n g
High Resolution
2 D Multi-Element Image
Brain Tissue Characterization,Identify Biomarkers and
Develop Insights into Disease Pathology
High Resolution
Optical Photography High Resolution
Micro-MR Image* *Imaging generously provided by Al Johnson’s Group at Duke University on 7T Instrument
G e n o m i c s a n d M o l e c u l a r I m a g i n g
Bioinformatics,Pathway Elucidation
Combination of Wet (Experiments) and Dry (Informatics) leading to
? discovery of biomarkers for in-vitro diagnostics
? discovery and optimization of targets for molecular imaging
Pathway Database
Analysis Engine Simulation Engine
Natural Language Database Wrappers
Internal/Proprietary Data
Wet Lab
Experiments
Summarized Mined Data
Testable Hypothesis
Pathway Informatics Platform
Viewable Pathway Maps Public Data
,G e n o m i c s a n d
M o l e c u l a r I m a g i n g,,,
T h e f u t u r e o f I m a g i n g,,,
T h e f u t u r e o f M e d i c i n e,
