Evaluating in vivo Biomarkers with MultiModality Molecular Imaging

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Evaluating in vivo Biomarkers with
Multi-Modality Molecular Imaging
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Biomarkers and Surrogate Endpoints
Biomarker A laboratory measurement or physical
sign used as an indication for a clinically
meaningful endpoint. Surrogate Endpoint A
laboratory measurement or physical sign used as a
substitute for a clinically meaningful endpoint.
Clinically Meaningful Endpoint
Surrogate Endpoint
Disease
Ideal Relationship Therapy induces change
surrogate endpoint, which reflects changes in
clinically meaningful endpoint.
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Biomarkers and Surrogate Endpoints
Biomarker A laboratory measurement or physical
sign used as an indication for a clinically
meaningful endpoint. Surrogate Endpoint A
laboratory measurement or physical sign used as a
substitute for a clinically meaningful endpoint.
Clinically Meaningful Endpoint
Surrogate Endpoint
Disease
Failure 1 Surrogate Endpoint not in causal
physiologic pathway. Example Focal white matter
lesions identified by MRI may not be responsible
for secondary progression in Multiple Sclerosis.
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Biomarkers and Surrogate Endpoints
Biomarker A laboratory measurement or physical
sign used as an indication for a clinically
meaningful endpoint. Surrogate Endpoint A
laboratory measurement or physical sign used as a
substitute for a clinically meaningful endpoint.
Clinically Meaningful Endpoint
Surrogate Endpoint
Disease
Failure 2 Surrogate Endpoint not in only causal
physiologic pathway. Example Some types of
chemotherapy can shrink tumors, but this has no
effect on metastasis and survival.
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Biomarkers and Surrogate Endpoints
Biomarker A laboratory measurement or physical
sign used as an indication for a clinically
meaningful endpoint. Surrogate Endpoint A
laboratory measurement or physical sign used as a
substitute for a clinically meaningful endpoint.
Clinically Meaningful Endpoint
Disease
Surrogate Endpoint
Failure 3 Surrogate Endpoint not in therapeutic
pathway. Example CXR reduces pneumonia, but no
short-term improvement in lung MRI.
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Biomarkers and Surrogate Endpoints
Biomarker A laboratory measurement or physical
sign used as an indication for a clinically
meaningful endpoint. Surrogate Endpoint A
laboratory measurement or physical sign used as a
substitute for a clinically meaningful endpoint.
Clinically Meaningful Endpoint
Surrogate Endpoint
Disease
Failure 4 Therapy acts after Surrogate
Endpoint. Example Recombinant Tissue Plasminogen
Activator rescues at risk tissue after ischemic
stroke, but no short-term improvement in MRI.
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Biomarkers and Surrogate Endpoints
Biomarker A laboratory measurement or physical
sign used as an indication for a clinically
meaningful endpoint. Surrogate Endpoint A
laboratory measurement or physical sign used as a
substitute for a clinically meaningful endpoint.
Clinically Meaningful Endpoint
Biomarker
Disease
Biomarker
Molecular Signature Multiple Molecular Biomarkers
MARTY PAGEL
Molecular Signatures may require 10 Molecular
Biomarkers
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Biomedical Imaging of Molecular Biomarkers
Reduces Animal Sacrifices
Conventional Serial Sacrifice
1 day
2 days
4 days
7 days
Molecular Imaging
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
1 day
2 days
4 days
7 days
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Biomedical Imaging of Molecular Biomarkers
Provides Better Sampling Over Time
Conventional Serial Sacrifice
day 1
day 2
day 3
day 4
day 5
day 6
day 7
day 8
Molecular Imaging
day 1
day 2
day 3
day 4
day 5
day 6
day 7
day 8
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Biomedical Imaging Modalities
No single modality is best for all molecular
biomarkersA trade-off between Resolution and
Sensitivity
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Biomedical Imaging Modalities
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Drug Discovery Development Pipeline
in vivo Pre-Clinical Testing is a critical
bottleneck

• 4 - 7 years
• Avg 478M

Clinical 200M Marketing gt 1B

• 2 - 3 years
• Avg 220M

• 1 - 2 years
• Avg 115M

in vitro Compound Screening
in vivo Pre-Clinical Testing
Target ID
Clincal Phase I
Clincal Phase II
Clincal Phase III
Clincal Phase IV

• In vivo Pre-clinical High Throughput Screening
  (HiTS)
• 22,000 25,000 human genes
• screening 1 dominant gene 20,000 animals
• screening 1 recessive gene gt 20,000 animals
• 5,000 10,000 drug targets
• screening 1 drug target 8,000 animals (plus
  1,000-3,000 humans for FDA-approved drug)

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Drug Discovery Development Pipeline
in vitro Compound Screening
in vivo Pre-Clinical Testing
Target ID
Clincal Phase I
Clincal Phase II
Clincal Phase III
Clincal Phase IV
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Molecular Imaging Visual representations of
cellular and molecular processes within intact
living organisms
Radiology
Molecular Imaging
Cell / Molecular Biology
Chemistry

• Multi-Modal Molecular Imaging
• Multiple agents in 1 animal in 1 detector
• 1 agent in multiple animals in 1 detector
• 1 agent in 1 animal in multiple detectors
• Multiple agents in multiple animals in multiple
  detectors

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Multiple agents in 1 animal in 1 detector
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Multiple agents in 1 animal in 1 detector
Predicting Topotecan Chemotherapy ResponseUsing
two PET imaging agents
Multi-SPECT agents Tc-99 In-111 I-125
Topo- red FDG black Drug and disease do not
coincide
FDG shows cancer
Topotecan chemotherapy Shows location of drug
Ray Muzic, Ph.D., CWRU
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Multiple agents in 1 animal in 1 detector
NMR Spectrum
PARACESTPARAmagnetic Chemical
ExchangeSaturation Transfer
RF Saturation
RF Saturation
RF Saturation
NH
H2O
Tm-DOTAM-Gly
O
N
H
H
O
O
O
N
H
O
H
N
N
O
Tm
O
without sat.
without sat.
N
N
H
N
H
O
with sat.
with sat.
O
O
O
H
H
H
N
O
HOH
HOH
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Multiple agents in 1 animal in 1 detector
PARACEST MRI Detection of Enzyme Activity
deconvolutions
PARACEST MRI
after reaction
before reaction
2nd agent(control agent)
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Multiple agents in 1 animal in 1 detector
PARACEST MRI detection of pH
amide
Yb-DO3a-oAA
amine
amine
amide
PARACEST
H
N
pH
tumor
pH Map
water
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pH 6.9 with agent
7
6
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Multiple agents in 1 animal in 1 detector
PARACEST MRI detection of pharmacokinetics
(Eu-DOTAMGly)96-G5 PAMAM Dendrimer
Tat-DEVD-(Tm-DOTA)
MR Water Signal
-51 ppm
Saturation Frequency (ppm)
flank tumor
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Multiple agents in 1 animal in 1 detector
PARACEST MRI detection of pharmacokinetics
(Eu-DOTAMGly)96-G5 PAMAM Dendrimer
Tat-DEVD-(Tm-DOTA)
flank tumor
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1 agent in Multiple Animals in 1 detector
Challenge 1 Limited Bore Diameter
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1 agent in Multiple Animals in 1 detector
Approach 2 1 agent in multiple animals in 1
detector
Challenge 2 Reduced Sensitivity and/or
Resolution with larger bore diameters
PET
MRI
Mouse Scanner
Mouse Brain Images
Human Scanner
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1 agent in Multiple Animals in 1 detector
Challenge 3 Physiological Monitoring
Secured to slide, nose cone, rectal thermometer
Placed in cradle, Pulse Oximiter, ECG,
respiration sensor, phantom
Tail vein catheter
Computer-Controlled Monitoring and Temperature
Stabilization
Side View
Top View
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1 agent in Multiple Animals in 1 detector
Yet in vivo imaging of Multiple Animals is
possible
BLI of anti-metastatic cancer therapy
MRI of anti-angiogenic cancer therapy
treated
untreated
treated
untreated
Modality Setup time Scan Time MRI 30 min
120 min BLI 5 min 20 min
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1 agent in Multiple Samples in 1 detector
HiTS of in vitro or ex vivo samples
HiTS of biological tissues in 24-well plates to
assess fat content2,592 samples/hour
HiTS of ex vivo legbones to assess
anti-metastatic chemotherapy 30 samples/hour
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1 agent in 1 animal in Multiple Detectors
Two combined modalities for molecular
biomarkersA compliment between SENSITIVITY and
RESOLUTION
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1 agent in 1 animal in Multiple Detectors
PET-CT and SPECT-CT
Detecting cell receptors with a labeled antibody
fragment
Tracking mesenchymal stem cells with a Na/I-
symporter reporter gene
PET / SPECT Molecular ImagingCT Anatomical
Imaging
Zhenghong Lee, Ph.D., CWRU
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1 agent in 1 animal in Multiple Detectors
MRI-PET
Monitoring of anti-tumor photodynamic therapy
Monitoring of anti-tumor photodynamic therapy
Heart
Tumor
Bladder
Overlay
MRI
PET
Overlay
MRI
PET
PET Molecular ImagingMRI Anatomical Imaging
Baowei Fei, Ph.D., CWRU
Zhenghong Lee, Ph.D., CWRU
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1 agent in 1 animal in Multiple Detectors
BLI-CT
Tracking mesenchymal stem cells in implanted
ceramic cubes
Stem Cells were transduced with Lentiviral SIN
vectors to incorporate reporter genes for BLI,
fluorescence, and PET imaging for cross-validation
BLI reporter gene
fluorescence imaging reporter gene
PET imaging reporter gene
Zhenghong Lee, Ph.D., CWRU
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1 agent in 1 animal in Multiple Detectors
Future Directionsmolecular imaging of
complimentary biomarkers
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Acknowledgements
Department of Radiology Zhenghong Lee,
Ph.D. Baowei Fei, Ph.D. Ray Muzic, Ph.D.
Department of BME Byunghee Yoo, Ph.D. Guanshu
Liu, M.S. Meser Ali, Ph.D. Yuguo Li, Ph.D. Rachel
Rosenblum, M.S.
Funding SourcesBreast Cancer Research Program,
DODNational Cancer Institute, NIHAmerican
Cancer SocietyBRTT Program, Ohio
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Evaluating in vivo Biomarkers with
Multi-Modality Molecular Imaging