Challenges and Opportunities for In Vivo Imaging In Oncology
Presented by Dan Sullivan to the NCI Board of Scientific Advisors, June 2002
See the Duke SAIRP web site for images from Mouse MRI Atlas http://wwwcivm.mc.duke.edu/
This slide set is abridged for web presentation.
In Vivo Imaging For Oncology
Devices (Hardware &Software)
Clinical Methodologies
•Screening •Diagnosis •Staging •Prognosis •Therapy Monitoring •Image-guided Rx Molecular Probes; Contrast Agents
Laboratory Methodologies
Study biology or interventions in animal models or humans (e.g., functional, in vivo genomics/proteomics; drug development)
Image Exploitation; Informatics
Outline
Overview Look back (portfolio review) Clinical and Laboratory imaging issues Molecular Imaging Image-guided interventions Conclusion
BIP Portfolio
140,000,000 120,000,000 100,000,000 80,000,000 60,000,000 40,000,000 20,000,000 0 Total PA $ Funded Total RFA $ Funded Other($) P01($) SBIR/STTR($) R01($)
96
97
98
99
00
FY
FY
FY
FY
FY
FY
01
BIP FY01 Portfolio
19 11 36 9 48
R01($) SBIR/STTR($) P01($) Other($) Total RFA $ Funded Total PA $ Funded
2
$ (M)
45
BIP FY01 RFA Funding
ACRIN (U01) SAIRP (R24) ICMIC Planning (P20) ICMIC (P50) Prostate Ca (R01; R33) Molecular Probes (R01) LIDC (U01) 10,884,947 6,894,782 6,355,434 6,211,663 2,634,319 2,415,395 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-Tx 76 cc Day 1 AC x1 79 cc Day 42 AC x3 26 cc Day 70 AC x4 25 cc Day 112 taxol x2 11 cc Day 178 taxol x4 6 cc
593
267 79 481 partial response to AC, regrowth on taxol final pathology - viable IDC and extensive DCIS
486
595
Univ. of Minnesota
Molecular Imaging Targets/Probes
MAb, Fragments Receptor Mapping Hormones Drugs and Ligands Peptides
Accumulation via Phosphorylation [18F]FDG
Internalization
glut 4
Enzyme Activity: Inhibition, Conc., Synthesis
Hexokinase DNA
Accumulation via DNA-Synthesis
Accumulation via AA Transport or Protein Synthesis
AAT mRNA
mRNA
Oligonucleotides mRNA Binding
Reporter Gene
DNA Reporter Probe
FDG-PET Monitoring Response to STI571 in GIST
Baseline
24 hours
7 days
2 months
5.5 months
Baseline
24 hrs
7 days
2 mos
5.5 mos
Dana-Farber Cancer Institute
In vivo imaging of protease (Cathepsin B) activity
2 mm
Light image
Human LX1 small cell lung tumor
NIRF image
Nature Biotech; 1999;17:375-378 Weissleder, Nature Biotech, 1999
10 nmole C-PGC, 24 hr
A Nanoscale, Targeted Liposome
Targeting MAb or ligand
High affinity metal binding
Gd encapsulation
Stanford Univ.
Phase 1, 2 Clinical Trials
MMPI and Cancer: Trials and Tribulations, Coussens, Science 2002
Targeted Agent Trials:
Problems:
Selecting patients Biologic endpoint assessment
Examples:
Matrix metaloproteinase inhibitors Anti-angiogenesis therapies 17-AAG (HSP90 inhibitor)
Construction of Multimeric Ligands
PEG
Image
Therapy
MSH CCK
Enk.
Gillies; U. AZ
Multimeric Specificity
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.
Image-guided Interventions
Future Potential
Surgical Robots
PET/CT
•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
Quantitative whole body imaging in 5 min …………or less
PET/CT-Based IMRT: Cervical Cancer 14 mm increase in axial extent of para-aortic lymph nodes
Imaging Modalities
Anatomy CT US MRI PET Optical Physiology Molecular
FMT imaging of CAB in 9L glioma
White light
a)
1cm
g)
Excitation light
1cm
b)
(nM)
h)
Emission light 1cm
(cm)
1cm
0
1
2
i)
Nature Med, 2002
Depth penetration in human tissues
108
Fluorescence strength (counts • sec-1 • mm-2)
106
104
30dB 20dB
102
10dB
100
10-2
10-4
Breast (40-70yrs) Breast (20-40yrs) Lung adult Muscle adult Brain adult
4 6 8 10 12 14 16 18 20
Ntziachristos, Ripoll, Weissleder. Optics Letters, 2002; 27:333-335
Depth (cm)
Whole-body Screening
Now: US – CT Germany – MRI Japan – FDG PET Future (US): PET/CT? MRI?
Skin Cancer Screening
“Optical screening”; < 2% chance of AK4 Ca; Marked “Overdiagnosis”
Rx is: “benign”, inexpensive, “Image-guided”.
MRI-Guided, Focused Ultrasound System
KHH99
MRI-guided, focused ultrasound therapy
Ductal invasive breast cancer Treatment plan
80 ultrasound foci
MRI-guided, focused ultrasound therapy
0
40°C
T
Temperature monitoring during therapy (SRTF, T1-w)
MRI-guided, focused ultrasound therapy Summary, properties
•Noninvasive through intact skin
•No scar •No anesthesia •No hospitalisation •Immediate Effect •Repeatable
Integrated Cancer Care
Detection Diagnosis Treatment
Detection
Diagnosis Treatment
data analysis sensing effector action judgment communication
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
In Vivo Imaging For Oncology
Go back and review slide 2
Acknowledgements
Ellen Feigal John Hoffman Edward Staab Barbara Croft Barbara Galen Anne Menkens Johnnie Smith Manuel Torres And Many Investigators. Laurence Clarke Gary Kelloff Houston Baker Keyvan Farahani Guoying Liu Richard Reba James Tatum Michael Vannier