Challenges and Opportunities for In Vivo Imaging In Oncology Slide Set

SLIDE 1: 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.

SLIDE 2: In Vivo Imaging For Oncology

• Topic 1: Devices (Hardware &Software)
• Topic 2: Research Methodologies: Study biology or interventions in animal models or humans (e.g., functional, in vivo genomics/proteomics; drug development)
• Topic 3: Clinical Methodologies
  -Screening
  -Diagnosis
  -Staging
  -Prognosis
  -Therapy Monitoring
  -Image-guided Rx
• Topic 4: Image Exploitation; Informatics These 4 topics all overlap with each other and combine together to make possible the use of Molecular Probes; Contrast Agents

SLIDE 3: Outline

• Overview
• Look back (portfolio review)
• Clinical and Laboratory imaging issues
• Molecular Imaging
• Image-guided interventions
• Conclusion

SLIDE 4: CIP Portfolio

A bar graph of dollars vs time shows the increasing amounts of funding in several categories:

• Total Program Announcement funding
• Total Request for Application funding
• Other funding
• P01 funding
• Small business funding
• R01 (investigator initiated grants) funding

SLIDE 5: CIP FY01 Portfolio

A pie chart shows the following categories and dollar amounts

• Total Program Announcement funding - $9 million
• Total Request for Application funding - $36 million
• Other funding - $2 million
• P01 funding - $19 million
• Small business funding - $11 million
• R01 (investigator initiated grants) funding - $48 million

SLIDE 6: CIP FY01 RFA Funding

Grant	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

SLIDE 7: 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

SLIDE 8: 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

SLIDE 9: 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?

SLIDE 10: Chemotherapy Response by MRI & MRS

• Images of tumor and MR spectra showing changes in spectral peaks during initial therapy and relapse.
• There was a partial response to AC, regrowth on taxol; the final pathology was viable IDC and extensive DCIS.
• Time frame is pre-taxol, days 1, 42, 70, 112 and 178.
• The patient had taxol before surgery because she had clinically palpable lymph nodes

Slide courtesy of the University of Minnesota

SLIDE 11: Molecular Imaging Targets/Probes

An illustration of molecular imaging targets/probes.

SLIDE 12: FDG-PET Monitoring Response to STI571 in GIST

Images are at baseline, 24 hours, 7 days, 2 months and 5.5 months.

SLIDE 13: No title

Schematic showing changes in a "smart" MRI probe, which becomes visible upon interaction with the target.

SLIDE 14: In vivo imaging of protease (Cathepsin B) activity

• Human LX1 small cell lung tumor
• 10 nmole C-PGC, 24 hr
• Slide shows light image and NIRF image.

Nature Biotech; 1999;17:375-378

SLIDE 15: A Nanoscale, Targeted Liposome

• An illustration of a liposome attached to antibodies or a ligand, carrying a bound metals and encapsulating Gadolinium

Slide courtesy of Stanford University

SLIDE 16: Molecular imaging of a_vb₃ in VX2 in Vivo

• Baseline images with regions of signal enhancement at 120 minutes overlayed
• Enhancement in surface of tumor is shown in one image
• Enhancement in the surface of the tumor is shown in the top panel, while enhancement in the vessel wall near the tumor is shown in the bottom panel.

SLIDE 17: Phase 1, 2 Clinical Trials

Graph of tumor progression over time showing:

• On the Y-axis benign, malignant, lethal tumor burden and
• On the line prevention, treat earlier, treat debulked disease, combination therapy, single agent
• On the X-axis the Natural Lifespan.

From: MMPI and Cancer: Trials and Tribulations, Coussens, Science 2002

SLIDE 18: Targeted Agent Trials:

Problems:

• Selecting patients
• Biologic endpoint assessment

Examples:

• Matrix metaloproteinase inhibitors
• Anti-angiogenesis therapies
• 17-AAG (HSP90 inhibitor)

SLIDE 19: Construction of Multimeric Ligands

Construction of Multimeric Ligands: illustration, from Gillies, U. Az.

SLIDE 20: Multimeric Specificity

Multimeric Specificity illustration.

SLIDE 21: 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.]

SLIDE 22: Location of Molecular Imaging Centers and Small Animal Imaging Research Programs on a map of the United States

Location of Molecular Imaging Centers and Small Animal Imaging Research Programs on a map of the United States

SLIDE 23: 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.

SLIDE 24: Small animal imaging for drug development (Demonstration Project: CIP, 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.

SLIDE 25: Image-guided interventions

4 images showing examples of the application and results of image-guided intervention

SLIDE 26: Future Potential of Image-Guided Intervention

Picture shows a brain image and a region to be treated superimposed on the head of a patient.

SLIDE 27: Surgical Robots

This figure illustrates several current or envisaged robotic systems that must work in unusual surgical environments.

• The PAKY robot currently under development by Drs. Stoianovici, Taylor and Whitcomb, at Johns Hopkins, is to be used for radiologically guided percutaneous needle insertion. This robot has received an IRB approval for renal access procedures. The future plan is to evolve this device into a miniature remote-center-of-motion (RCM) manipulator with high tool tip angular mobility (>90 degrees) and precision (2-25 mm over 10-15 cubic work volumes).
• The long term goal is to employ the PAKY and mini-RCM devices in hostile environments such as in x-ray and computerized tomography machines.
• The slide also illustrates MR compatible robot under development and evaluation by Dr. Kikinis. This robotic system will soon be employed at Brigham and Women’s Hospital. The proposed robotic systems will employ non-ferromagnetic materials will work in the open magnet machine. Future MR compatible robot will use the MR tagging and MR coils developed under the previous sub-thrust.

SLIDE 28: PET/CT

PET/CT Illustration

• 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

SLIDE 29: No title

Quantitative whole body imaging in 5 min …………or less

SLIDE 30: PET/CT-Based IMRT: Cervical Cancer

• 14 mm increase in axial extent of para-aortic lymph nodes
• Images of sagittal, coronal, and transaxial sections

SLIDE 31: Imaging Modalities

• Bar graph showing how CT, Ultrasound, MRI, PET and Optical imaging show Anatomy, Physiology, and Molecular information
• CT is mostly anatomical
• US is mostly anatomical, going a bit farther toward representing physiology
• MRI again is mostly anatomical, going yet a bit farther toward representing physiology
• PET represents physiology and molecular biology
• Optical represents molecular biology

SLIDE 32: FMT imaging of CAB in 9L glioma

• NIRF tomographer built at CMIR
• Shows images of tumor under room light, excitation light and emission light.

From Nature Med 2002.

SLIDE 33: Depth penetration in human tissues

Graph of Fluorescence Strength (counts/sec-mm-squared) vs. Depth (cm) Lines representing Breast of 40-70 year old, Breast of 20-40 year old, Adult Lung, Adult Muscle, and Adult Brain from Ntziachristos, Ripoll, Weissleder, Optics Letters, 2002; 27: 333-335.

SLIDE 34: New York Times Article

Image of on-line New York Times article by Gina Kolata, May 27, 2002, titled "Cheaper Body Scans Spread, Despite Doubts"

SLIDE 35: Whole-body Screening

Now:

• US - CT
• Germany - MRI
• Japan - FDG PET

Future (US):

• PET/CT?
• MRI?

SLIDE 36: Skin Cancer Screening

Showing "optical screening" by human eye and small hand-held instrument

• "Optical screening";
• Small Handheld Instrument: Rx is: "benign", inexpensive, "image-guided".

SLIDE 37: MRI-Guided, Focused Ultrasound System

Schematic of the system, showing the MRI magnet, surface coil, PVC membrane, ultrasound beams, transducer, water

SLIDE 38: MRI-guided, focused ultrasound therapy

Images of breast showing ductal invasive breast cancer and the planned focus for therapy

SLIDE 39: MRI-guided, focused ultrasound therapy

Showing temperature monitoring during therapy

SLIDE 40: MRI-guided, focused ultrasound therapy Summary, properties

• Noninvasive through intact skin
• No scar
• No anesthesia
• No hospitalisation
• Immediate Effect
• Repeatable

SLIDE 41: Integrated Cancer Care

proceeds from DETECTION through DIAGNOSIS through TREATMENT

• DETECTION involves sensing and communication,
• DIAGNOSIS involves data analysis,
• TREATMENT involves judgment and effector action

SLIDE 42: 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

SLIDE 43: 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

SLIDE 44: In Vivo Imaging For Oncology

Review of Slide 2

• Topic 1: Devices (Hardware &Software)
• Topic 2: Research Methodologies: Study biology or interventions in animal models or humans (e.g., functional, in vivo genomics/proteomics; drug development)
• Topic 3: Clinical Methodologies
  -Screening
  -Diagnosis
  -Staging
  -Prognosis
  -Therapy Monitoring
  -Image-guided Rx
• Topic 4: Image Exploitation; Informatics These 4 topics all overlap with each other and combine together to make possible the use of Molecular Probes; Contrast Agents

SLIDE 45: Acknowledgements

Ellen Feigal
Laurence Clarke
John Hoffman
Gary Kelloff
Edward Staab
Houston Baker
Barbara Croft
Keyvan Farahani
Barbara Galen
Guoying Liu
Anne Menkens
Richard Reba
Johnnie Smith
James Tatum
Manuel Torres
Michael Vannier
And Many Investigators.