# Presentation: 905619

## 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

## In Vivo Imaging For Oncology

_**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 Oncology**_

_**Devices**_
**(Hardware**
**&Software)**

_**Molecular**_
_**Probes**_**;**
**Contrast**
**Agents**

_**Image**_
_**Exploitation;**_
**Informatics**

**Notes:**
In Vivo Imaging For Oncology
Topic One: 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

## Outline

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

**Notes:**
Outline
Overview
Look back (portfolio review)
Clinical and Laboratory imaging issues
Molecular Imaging
Image-guided interventions
Conclusion

## BIP Portfolio

**Notes:**
BIP 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

## BIP FY01 Portfolio

**Notes:**
BIP 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

## 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 |

**Notes:**
BIP FY01 RFA Funding Dollars
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**

**Notes:**
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**

**Notes:**
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?**

**Notes:**
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

**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**

**partial response to AC, regrowth on taxol**
**final pathology - viable IDC and extensive DCIS**

**593**

**486**

**267**

**79**

**481**

**595**

**Univ. of Minnesota**

**Notes:**
Chemotherapy Response by MRI and 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

## Molecular Imaging Targets/Probes

**Molecular Imaging Targets/Probes**

**mRNA**

**DNA**

**mRNA**

**Receptor Mapping**

**Enzyme Activity:**
**Inhibition, Conc.,**
**Synthesis**

**Accumulation via**
**AA Transport  or**
**Protein Synthesis**

**Oligonucleotides**
**mRNA Binding**

**Reporter Probe**

**Reporter Gene**

**DNA**

**AAT**

**glut 4**

**Accumulation via**
**Phosphorylation**
**[****18****F]FDG**

**MAb,**** ****Fragments**

**Hormones**

**Drugs and Ligands**

**Peptides**

**Accumulation via**
**DNA-Synthesis**

**Internalization**

**Hexokinase**

**Notes:**
A cartoon of molecular imaging targets/probes

## FDG-PET Monitoring Response to STI571 in GIST 

**FDG-PET Monitoring Response to STI571 in GIST **

**Baseline****	****   **_**24 hrs**_**	****  7 days         2 mos         5.5 mos**

**Dana-Farber Cancer Institute**

**Notes:**
FDG-PET Monitoring Response to STI571 in GIST
Images are at baseline, 24 hours, 7 days, 2 months and 5.5 months

## Slide 13

**Notes:**
Schematic showing changes in a “smart” MRI probe, which becomes visible upon interaction with the target

## In vivo imaging of protease 

**NIRF image**

***In vivo***** imaging of protease **
**(Cathepsin B) activity**

**Human LX1 small cell lung tumor**
- 10 nmole C-PGC, 24 hr

- Weissleder, Nature Biotech, 1999

**Nature Biotech; 1999;17:375-378**

**Notes:**
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

## A Nanoscale, Targeted Liposome

**A Nanoscale, Targeted Liposome**

**Targeting**
**MAb or ligand**

**High affinity**
**metal binding**

**Gd**
**encapsulation**

**Stanford Univ.**

**Notes:**
A Nanoscale, Targeted Liposome
A cartoon of a liposome attached to antibodies or a ligand, carrying a bound metals and encapsulating Gadolinium
Slide courtesy of Stanford University

## Slide 16

**Notes:**
Molecular imaging of av3 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.  

## Phase 1, 2 Clinical Trials

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

**Notes:**
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

## Targeted Agent Trials:

**Problems:**
**Selecting patients**
**Biologic endpoint assessment**
**Examples:**
**Matrix metaloproteinase inhibitors**
**Anti-angiogenesis therapies**
**17-AAG (HSP90 inhibitor)**

**Notes:**
Targeted Agent Trials:
Problems
	Selecting patients
	Biologic end point assessment
Examples
	Matrix metalloproteinas inhibityors
	Anti-angiogenesis therapies
	17-AAG (HSP90 inhibitor)

## Construction ofMultimeric Ligands

**Gillies; U. AZ**

**Notes:**
Construction of Multimeric Ligands: cartoon, from Gillies, U. Az.

## Multimeric Specificity

**Notes:**
Multimeric Specificity cartoon

## 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.]**

**Notes:**
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

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

## 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.**

**Notes:**
Small animal imaging for drug development
	(Demonstration Project: BIP, DTP, CTEP)
Anti-angiogenesis first model system;
NCI will supply animal, drugs and imaging protocol to contractors;
tissues will be returned to NCI for standardized processing.

## 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.**

**Notes:**
Small animal imaging for drug development
	(Demonstration Project: BIP, DTP, CTEP)
Anti-angiogenesis first model system;
NCI will supply animal, drugs and imaging protocol to contractors;
tissues will be returned to NCI for standardized processing.

## Image-guided Interventions

**Image-guided Interventions**

**Notes:**
Image-guided interventions 
4 images showing examples of the application and results of image-guided intervention

## Future Potential

**Notes:**
Future Potential of Image-Guided Intervention
Picture shows a brain image and a region to be treated superimposed on the head of a patient.

## Surgical Robots

**Notes:**
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.

## 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**

**PET/CT**

## Quantitative whole body imaging in 5 min

**Quantitative whole body imaging in 5 min**
**............****or less**

**Notes:**
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

**Notes:**
PET/CT-Based IMRT: Cervical Cancer
14 mm increase in axial extent of para-aortic lymph nodes
Images of sagittal, coronal, and transaxial sections

## Imaging Modalities

**Anatomy**

**Physiology**

**Molecular**

**CT**

**US**

**MRI**

**PET**

**Optical**

**Notes:**
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

## FMT imaging of CAB  in 9L glioma

**Notes:**
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.

## Depth penetration in human tissues

**Depth penetration in human tissues**

**Ntziachristos, Ripoll, Weissleder. Optics Letters, 2002; 27:333-335**

**Notes:**
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

**Notes:**
Image of on-line New York Times article by Gina Kolata, May 27, 2002, titled “Cheaper Body Scans Spread, Despite Doubts”

## Whole-body Screening

**Now:**
**US – CT**
**Germany – MRI**
**Japan – FDG PET**
**Future (US):**
**PET/CT?**
**MRI?**

**Notes:**
Whole-body Screening
Now: 
US - CT
Germany - MRI
Japan - FDG PET

Future (US):
PET/CT?
MRI?

## Skin Cancer Screening

**Skin Cancer Screening**

**“****Optical screening”;**
**< 2% chance of AK******** Ca;**
**Marked “Overdiagnosis”**

**Rx is: “benign”,**
**inexpensive,**
**“****Image-guided”.**

**Notes:**
Skin Cancer Screening
Showing “optical screening” by human eye and small hand-held instrument
“Optical screening”; < 2% chance of AK4 Ca; leads to marked “Overdiagnosis”
Small Handheld Instrument: Rx is: “benign”, inexpensive, “image-guided”.

## MRI-Guided, Focused Ultrasound System

- KHH99

**Notes:**
MRI-Guided, Focused Ultrasound System
Schematic of the system, showing the MRI magnet, surface coil, PVC membrane, ultrasound beams, transducer, water 

## MRI-guided, focused ultrasound therapy

**Treatment plan**** **

**Ductal invasive**
**breast cancer**

**80 ultrasound foci**

**MRI-guided, focused ultrasound therapy**

**Notes:**
MRI-guided, focused ultrasound therapy
Images of breast showing ductal invasive breast cancer and the planned focus for therapy

## MRI-guided, focused ultrasound therapy

**MRI-guided, focused ultrasound therapy**

**Temperature monitoring during therapy**
**(SRTF, T1-w) **

**Notes:**
MRI-guided, focused ultrasound therapy
Showing temperature monitoring during therapy 

## Noninvasive through intact skin

**No scar**
**No  anesthesia**
**No hospitalisation**
**Immediate Effect**
**Repeatable**

**MRI-guided, focused ultrasound therapy**
**Summary, properties**

**Notes:**
MRI-guided, focused ultrasound therapy
Summary, properties
Noninvasive through intact skin
No scar
No  anesthesia
No hospitalisation
Immediate Effect
Repeatable

## Integrated Cancer Care

**      ****Diagnosis**

**        ****Treatment**

**Detection**

**Detection**

**        ****Diagnosis**

**       ****Treatment**

**sensing**

**communication**

**judgment**

**data analysis**

**effector action**

**Unconventional Innovations Web Site:**

**Notes:**
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

## 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**

**Notes:**
UIP Awardees FY 99
1.  U of Michigan, James Baker, M.D.  
Nano-scale based dendrimer devices
2. U of Penn, Britton Chance, Ph.D.   
Near-infrared detector and contrast agents for molecular targets 
3. U of Alabama at Birmingham, David Curiel, M.D.  
Genetic approaches to tumor detection and intervention
4. U of Cal at Davis, N.C. Luhmann, Jr.Ph.D.
Compton light source for high-contrast X-rays 
5. 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**

**Notes:**
UIP Awardees FY 2000
1. U of Washington, Kirk W. Beach, M.D., Ph.D.  
Ultrasound detection of tissue pulsatility
2.  U of Pittsburgh, Daniel Farkas, Ph.D. 
Optical imaging platform for mesoscopic imaging 
3.U of Michigan, Raoul Kopelman, Ph.D.
Dynamic nano-particles for detection and treatment
4. 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

**Notes:**
In Vivo Imaging For Oncology
Topic One: 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

## 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.***

**Notes:**
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.