Challenges and Opportunities for In Vivo Imaging In

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) Laboratory Methodologies Clinical Methodologies • Screening • Diagnosis • Staging • Prognosis • Therapy Monitoring • Image-guided Rx Molecular Probes; Contrast Agents Image Exploitation; Informatics Study biology or interventions in animal models or humans (e. g. , functional, in vivo genomics/proteomics; drug development)

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

BIP Portfolio

BIP FY 01 Portfolio

BIP FY 01 RFA Funding ACRIN (U 01) SAIRP (R 24) ICMIC Planning (P 20) ICMIC (P 50) Prostate Ca (R 01; R 33) Molecular Probes (R 01) LIDC (U 01) 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 n Rigorous methodology Two U 01’s will not be renewed Additional venues for diagnostic trials: e. g. , ACOSOG; R 01’s; R 33’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 x 1 79 cc 593 486 Day 42 AC x 3 26 cc Day 70 AC x 4 25 cc Day 112 taxol x 2 11 cc 267 79 481 partial response to AC, regrowth on taxol final pathology - viable IDC and extensive DCIS Day 178 taxol x 4 6 cc 595 Univ. of Minnesota

Molecular Imaging Targets/Probes MAb, Fragments Accumulation via Phosphorylation [18 F]FDG glut 4 Receptor Mapping Hormones Drugs and Ligands Peptides Enzyme Activity: Inhibition, Conc. , Synthesis Internalization Hexokinase DNA Accumulation via AA Transport or Protein Synthesis Reporter Gene AAT Accumulation via DNA-Synthesis m. RNA Oligonucleotides m. RNA Binding m. RNA DNA Reporter Probe

FDG-PET Monitoring Response to STI 571 in GIST 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 LX 1 small cell lung tumor 10 nmole C-PGC, 24 hr NIRF image Nature Biotech; 1999; 17: 375 -378 Weissleder, Nature Biotech, 1999

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: n n Selecting patients Biologic endpoint assessment Examples: n n n Matrix metaloproteinase inhibitors Anti-angiogenesis therapies 17 -AAG (HSP 90 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 R 01, 1993 • Now commercially available • ~ 150 expected to be sold by 2003 • Townsend has received R 33 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 9 L glioma White light a) 1 cm g) Excitation light 1 cm b) (n. M) h) Emission light 1 cm (cm) 1 cm 0 1 2 i) Nature Med, 2002

Depth penetration in human tissues Fluorescence strength (counts • sec-1 • mm-2) 108 106 104 30 d. B 20 d. B 102 10 d. B 100 10 -2 Breast (40 -70 yrs) Breast (20 -40 yrs) Lung adult Muscle adult Brain adult 10 -4 4 6 8 10 12 14 Depth (cm) Ntziachristos, Ripoll, Weissleder. Optics Letters, 2002; 27: 333 -335 16 18 20

Whole-body Screening Now: US – CT Germany – MRI Japan – FDG PET Future (US): PET/CT? MRI?

Skin Cancer Screening “Optical screening”; < 2% chance of AK 4 Ca; Marked “Overdiagnosis” Rx is: “benign”, inexpensive, “Image-guided”.

MRI-Guided, Focused Ultrasound System KHH 99

MRI-guided, focused ultrasound therapy Ductal invasive breast cancer Treatment plan 80 ultrasound foci

MRI-guided, focused ultrasound therapy 0 T Temperature monitoring during therapy (SRTF, T 1 -w) 40°C

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 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, 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