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Challenges and Opportunities
for In Vivo Imaging
In Oncology
This slide set is abridged for web presentation.
See the Duke SAIRP web site for images from Mouse MRI Atlas
http://wwwcivm.mc.duke.edu/
Presented by Dan Sullivan to the NCI Board of Scientific Advisors, June 2002
Clinical Methodologies•Screening•Diagnosis•Staging•Prognosis•Therapy Monitoring•Image-guided Rx
Laboratory Methodologies
Study biology or interventions in animal models or humans (e.g., functional, in vivo genomics/proteomics; drug development)
In Vivo Imaging For OncologyDevices
(Hardware&Software)
MolecularProbes;ContrastAgents
ImageExploitation;Informatics
OutlineOverview
Look back (portfolio review)
Clinical and Laboratory imaging issues
Molecular Imaging
Image-guided interventions
Conclusion
BIP Portfolio
0
20,000,000
40,000,000
60,000,000
80,000,000
100,000,000
120,000,000
140,000,000
FY96
FY97
FY98
FY99
FY00
FY01
Total PA $ FundedTotal RFA $ FundedOther($)P01($)SBIR/ STTR($)R01($)
BIP FY01 Portfolio
$ (M)
48
11
19 2
36
9
45
R01($)SBIR/ STTR($)P01($)Other($)Total RFA $ FundedTotal PA $ Funded
BIP FY01 RFA Funding
ACRIN (U01) 10,884,947
SAIRP (R24) 6,894,782
ICMIC Planning (P20) 6,355,434
ICMIC (P50) 6,211,663
Prostate Ca (R01; R33) 2,634,319
Molecular Probes (R01) 2,415,395
LIDC (U01) 1,326,774
Imaging in Clinical Trials
ACRIN – more later Rigorous methodology
Two U01’s will not be renewed
Additional venues for diagnostic trials: e.g., ACOSOG; R01’s; R33’s
Imaging in Clinical Trials
More integration of imaging studies in CTEP trials – especially in the neoadjuvant setting
Inter-group Imaging Council
Imaging Cores in Cancer Centers
Access to imaging resources is inadequate
Monitoring Response to Therapy
RECIST Criteria -- good start; volumetric would be better.
Need Functional Response Indicators – “molecular imaging”.
Generic, “downstream” indicator vs. specific, targeted probe?
Chemotherapy Response by MRI & MRS
1 wk pre-Tx76 cc
Day 1 AC x179 cc
Day 42AC x326 cc
Day 70AC x425 cc
Day 112taxol x2
11 cc
Day 178taxol x4
6 cc
partial response to AC, regrowth on taxolfinal pathology - viable IDC and extensive DCIS
593 486 267 79 481 595
Univ. of Minnesota
Molecular Imaging Targets/Probes
mRNA
DNA
mRNA
Receptor Mapping
Enzyme Activity:Inhibition, Conc.,Synthesis
Accumulation viaAA Transport orProtein Synthesis Oligonucleotides
mRNA Binding
Reporter ProbeReporter Gene DNA
AAT
glut 4
Accumulation viaPhosphorylation[18F]FDG
MAb, FragmentsHormones
Drugs and LigandsPeptides
Accumulation viaDNA-Synthesis
InternalizationInternalization
HexokinaseHexokinase
FDG-PET Monitoring Response to STI571 in GIST
Baseline 24 hrs 7 days 2 mos 5.5 mos
Dana-Farber Cancer Institute
Light image NIRF image
In vivo imaging of protease (Cathepsin B) activity
Human LX1 small cell lung tumor 10 nmole C-PGC, 24 hr
2 mm
Weissleder, Nature Biotech, 1999Nature Biotech; 1999;17:375-378
A Nanoscale, Targeted Liposome
TargetingMAb or ligand
High affinitymetal binding Gd
encapsulation
Stanford Univ.
Targeted Agent Trials:
Problems: Selecting patients Biologic endpoint assessment
Examples: Matrix metaloproteinase inhibitors Anti-angiogenesis therapies 17-AAG (HSP90 inhibitor)
Nano-engineered Optical Agents
Emission spectra can be “tuned”
[Nanotechnology: the creation of functional materials, devices and systems through control of matter at the scale of 1 to 100 nanometers, and the exploitation of novel properties and phenomena at the same scale.]
DCIDE
Development of Clinical Imaging Drugs and Enhancers
Purpose: Facilitate pre-clinical development of promising imaging agents by providing the resources needed for successful IND application.
Small Animal Imaging for Drug Development (Demonstration Project:
BIP, DTP, CTEP)
anti-angiogenesis first model system;NCI will supply the animals, drugs, and imaging protocol, to contractors;tissues will be returned to NCI for standardized processing.
•David Townsend, U
Pitt.•NCI R01, 1993•Now commercially
available• ~ 150 expected to be
sold by 2003•Townsend has
received R33 for
second-generation•Higher-resolution,
faster acquisition PET•Sub 4-minute scans
PET/CT
FMT imaging of CAB in 9L glioma
1cm
1cm
1cm
1cm
a)
b)
0 1 2
(cm)
(nM)
g)
h)
i)
Emission light
White light
Excitation light
Nature Med, 2002
Depth (cm)
4 6 8 10 12 14 16 18 20
100
102
104
106
108
Flu
ores
cenc
e st
reng
th (
coun
ts •
sec
-1 •
mm
-2)
30dB
20dB
10dB
Breast (40-70yrs)Breast (20-40yrs)Lung adultMuscle adultBrain adult
10-4
10-2
Depth penetration in human tissues
Ntziachristos, Ripoll, Weissleder. Optics Letters, 2002; 27:333-335
Skin Cancer Screening
“Optical screening”;< 2% chance of AK Ca;Marked “Overdiagnosis”
Rx is: “benign”,inexpensive,
“Image-guided”.
Treatment plan Ductal invasivebreast cancer
80 ultrasound foci
MRI-guided, focused ultrasound therapy
•Noninvasive through intact skin
•No scar
•No anesthesia
•No hospitalisation
•Immediate Effect
•Repeatable
MRI-guided, focused ultrasound therapySummary, properties
Integrated Cancer Care
Diagnosis TreatmentDetection
Detection Diagnosis Treatment
sensing
communication judgment
data analysis effector action
Unconventional Innovations Web Site:
UIP Awardees FY 99
U of Michigan, James Baker, M.D. Nano-scale based dendrimer devices
U of Penn, Britton Chance, Ph.D. Near-infrared detector and contrast agents for molecular targets
U of Alabama at Birmingham, David Curiel, M.D. Genetic approaches to tumor detection and intervention
U of Cal at Davis, N.C. Luhmann, Jr.Ph.D.Compton light source for high-contrast X-rays;
NASA Ames Research Center, Meyya Meyyapan, Ph.D.Carbon nanotube-based biosensor and prototype biosensor catheter
UIP Awardees FY 2000
U of Washington, Kirk W. Beach, M.D., Ph.D. Ultrasound detection of tissue pulsatility
U of Pittsburgh, Daniel Farkas, Ph.D. Optical imaging platform for mesoscopic imaging
U of Michigan, Raoul Kopelman, Ph.D.Dynamic nano-particles for detection and treatment
Barnes-Jewish Hospital, Gregory M. Lanza, M.D., .Ph.D.Targeted Nanoparticle Emulsion for Molecular Imaging and Local Drug Delivery
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