November 15
In Vivo Molecular Imaging
Wednesday, November 15
7:45 am Breakfast Workshop
The Simultaneous Measurement of Blood Flow and Biochemistry via Optical Imaging
David R. Vera, Ph.D., Professor, Moores UCSD Cancer Center, University of California, San Diego
Imaging via time domain optical imaging provides a unique opportunity to simultaneously measure multiple biochemical and or physiologic parameters. There are two features of time domain (TD) methodology that enable the multiple measurements. First, TD permits image reconstruction, which provides correction for depth-effects. This correction properly prepares the imaging data for kinetic modeling, which can be employed to measure multiple parameters. Second, TD-based optical imaging offers the opportunity to inject multiple probes with differing optical lifetimes. This strategy, for example, would permit the simultaneous injection of two probes: one to measure blood flow and the other to measure a biochemical marker, such as receptor density or affinity. Examples will be provided for this strategy, as well as, the use of kinetic modeling. These methods, and consequently the need for time-domain imaging, will be required to properly interpret preclinical imaging for drug development, where a constant problem is the separation of delivery and biochemistry. For example, if an optical image of a tumor has decreased in fluorescence intensity after a therapy protocol, was the decreased uptake by the probe due to decreased tumor blood flow or a decrease in the density of the biochemical marker within the tumor? |
Sponsored by
|
|
8:25 Chairperson’s Remarks
| Keynote Presentation |
8:30
Target-cell Specific in vivo Molecular Imaging of Cancer using Multicolor Activatable Fluorescence
Probes
Hisataka Kobayashi, M.D., Ph.D., Chief Staff Scientist, Molecular Imaging Program/Center for Cancer Research/National Cancer Institute/NIH |
|
Imaging in Neurology
9:15 Development of New Probes and Techniques for Optical Imaging in Alzheimer’s Disease
Brian Bacskai, Ph.D., Assistant Professor, Department of Neurology, Massachusetts General Hospital/Harvard University
Alzheimer’s disease is characterized by the progressive accumulation of senile plaques. An imaging technique sensitive to amyloid-beta accumulation in the brain would allow early diagnosis and effective drug screening with longitudinal monitoring. Recent success with radioligands for PET imaging are encouraging, but the expense and limited availability hinder widespread imaging. Similarly, microPET in animal models with current PET ligands do not seem to work. An optical approach for non-invasive imaging in animals, and ultimately humans, would be relatively inexpensive and widely available. Our goals are to develop novel small molecule contrast agents that are near infrared fluorescent, cross blood-brain barrier, and target Abeta specifically. In combination, we are developing novel optical tomographic approaches to detect these agents with high sensitivity and high spatial resolution in living animals. With an orchestrated multidisciplinary approach, we expect to facilitate in vivo drug testing in animal models, and perhaps diagnose early stage Alzheimer’s disease in humans.
9:45 Strategies for Rapid Human CNS Biomarker Development and Application
John Seibyl, M.D., Senior Scientist, Nuclear Imaging, Molecular Neuroimaging
The purpose of this talk is to describe new vertically integrated models of CNS biomarker development and implementation in human drug development trials using PET and SPECT. This describes focused primate screening methods, strategies for optimizing quanitative outcome measures, and large-scale implementation in Phase IIb- IV clinical trials in multicenter imaging settings with incorporation of Good Imaging Practices (GIP) and harmonization of imaging across different cameras.
10:15 Coffee Break in Exhibit Hall
11:00 Multimodality Imaging of Alzheimer’s Disease: From Mouse to Man
Thomas Krucker, Ph.D., Head Molecular Imaging, Discovery Technologies, Novartis Institutes for BioMedical Research, Inc. (NIBRI)
Alzheimer’s disease (AD) is a neurodegenerative dementia characterized by neuronal loss, amyloid deposition, and neurofibrillary tangles. Clinically, the most notable feature is a characteristic cognitive impairment. Vascular factors have been associated with the development of multi-infarct dementia, and might also be implicated in the pathogenesis of the disease. Despite decades of intense research, there are no cures for AD. However, it has accelerated the insights into the biology of the disease and provided new aspects of the molecular underpinnings, including vast information about the genetics and associated risk factors. We are using different lines of mutant mice modeling Alzheimer’s disease to study disease progression, determine early diagnosis, and test potential therapeutic interventions. Exploring new concepts and imaging strategies allowed us to visualize vascular alterations and changes in blood flow at early stages of the disease. In addition, we now can successfully monitor non-invasively amyloid deposition, a hallmark of Alzheimer’s disease, using novel probe technology. Although challenging, translation of such strategies into clinical applications have great potential. First attempts and possible alternatives will be discussed.
11:30 A High-Throughput Molecular Imaging Screen to Monitor Therapeutic Response
In Vivo
H. Charles Manning, Ph.D., Assistant Professor of Radiology, Vanderbilt University Institute of Imaging Sciences (VUIIS); Assistant Professor of Neurosurgery, Vanderbilt University Medical Center
In this presentation we will demonstrate that molecular imaging will facilitate real-time efficacy monitoring in small animal models of experimental auto-immune encephalomyelitis (EAE) and some forms of cancer. We have prepared a panel of complementary NIR-based imaging probes that give a physiologically relevant readout allowing observation of therapeutic response. These probes measure epidermal growth factor receptor (EGFR) expression (NIR-EGF), glucose metabolism (NIR-GLC), steroidogenesis (NIR-conPK11195), DNA replication (NIR-d-thymidine) and angiogenesis (NIR-VEGF) and apoptosis (NIR-Annexin-V). We will show that NIR-conPK11195 and NIR-GLC mimic the translational probes 18FDG and 11C-PK11195 already in use in the clinic and by utilizing our novel Lanthanide chelate chemistry, we can prepare PET/SPECT versions of the other optical probes for translation of the full efficacy screen to the clinic. It will be shown that the screen is broadly applicable to small animal disease models and can be used to accelerate the pre-clinical evaluation of biological response modifiers (BRMs) and conventional therapeutics.
12:00 Lunch on your own (Luncheon Workshop Sponsorship Available)
1:25 Chairperson’s Remarks
Imaging in Cardiology
1:30
Targeting and Tracing Antigens in Live Cells with Fluorescent Nanobodies
Dr. Ulrich Rothbauer, Senior Scientist, Department Biologie II, Ludwig Maximilians University
Fresh from the Press: Brief Communications in Nature Methods, November
2006
2:00 Functional and Molecular Imaging with Micro-Ultrasound
F. Stuart Foster, Ph.D., Department of Medical Biophysics, University of Toronto, Sunnybrook Health Sciences Centre, Canada
This presentation will describe the development, implementation, and application of high frequency contrast enhanced micro-ultrasound to extract quantitative measures of functional and molecular targets in preclinical research. The development of targeted microbubble contrast agents will be described. Applications of this technology to the study of tumor microcirculation and therapeutic response to antiangiogenic agents will also be presented. Untargeted contrast permits the evaluation the morphology and hemodynamics of various tumor models. These methods allow, for the first time, realtime in vivo visualization of the true microcirculation. Molecular studies of targeted molecular targets such as VEGFR-2 will be presented. These results show the ability of micro-ultrasound not only to detect expression of VEGFR-2 in experimental mouse tumors but also to do so with resolution nearly an order of magnitude better than micro PET. The feasibility of clinical translation of these approaches will also be discussed.
Imaging in Oncology
2:30 Molecular Diapeutics-New Approaches to Cancer Detection and Treatment
Jamey Weichert, Ph.D., Associate Professor, Department of Radiology, Medical Physics and Pharmaceutics, University of Wisconsin
We have developed a radioiodinated phospholipid ether analog that has displayed striking tumor uptake and prolonged retention in 30/30 animal and human tumor models to date. We have now successfully labeled this agent with iodine-124 a new PET isotope with a 4 day half-life. A phase 1 pharmacokinetic and imaging trial has been initiated in lung cancer patients and shown similar tumor avidity and retention. When labeled with iodine-125, the agent, NM404, has afforded significant tumor regression in both human A549 lung and PC-3 prostate tumor models in mice following a single i.v. injection. The agent does not localize in benign or preneoplastic lesion nor in inflammatory lesions and is thus only selectively retained in malignant tumor cells. The hypothesis behind the prolonged malignant cell retention is that malignant cells lack an isoform of phospholipase-D (PLD) relative to normal host tissue cells. Because they lack this metabolic enzyme, the agent becomes trapped in tumor cells but not in normal cells. Recently, utilizing laser capture microdissection techniques, we have found that human pancreatic tumor cells contain 275-fold less PLD than normal pancreatic host cells. This diapeutic agent is designed to exploit this difference in malignant tumor and normal cells.
3:00 Networking Refreshment Break
3:30 Clinical and Preclinical Application of HER2-Specific Affibody Molecules for Diagnosis of Recurrent HER2 Positive Breast Cancer by SPECT or PET/CT
Dr. Anders Wennborg, Head, Pharmacology, Affibody AB
The HER2-specific Affibody molecule ZHER2:342 belongs to a novel class of small non-immunoglobulin affinity ligands with high target-binding affinity and specificity. Preclinical characterization of radiolabeled HER2-Scan in mice bearing HER2-expressing tumor xenografts showed high specific tumor targeting with 23 % IA/g at 1 hour post injection, rapid biodistribution kinetics and blood clearance and allowed high contrast gamma camera imaging as early as 1 hour post injection. For the first time in human study, we evaluate the use of labeled HER2-Scan to specifically detect and stage HER2-expressing metastatic lesions in patients with recurrent breast cancer. Injection of a microdose (<100 µg) of 111In or 68Ga-labeled HER2-Scan (110-130 MBq) resulted in high quality SPECT and PET/CT images enabling the detection of small lesions(12-14 mm) after 2-3 hours post injection. Patients were carefully monitored and no adverse effects were observed.
4:00 An Early MRI Biomarker of Cancer Treatment Response
Brian Ross, Ph.D., Professor, Department of Radiology, University of Michigan
This presentation will detail how the functional diffusion map (fDM) can be used as an imaging biomarker for quantification of early treatment response in solid tumors. In brief, changes in tumor MRI diffusion values were found to be highly correlative with drug dose and biological outcome measures revealing fDM is an effective early biomarker for prediction of efficacy in rodents and in human brain tumor patients. Thus, early fDM measurements can be used to provide an early biomarker of response in patients thus allowing for an opportunity to individualize treatment.
4:30 Engineered Antibodies for Imaging Cell Surface Phenotype
Tove Olafsen, Ph.D., Associate Researcher, Department of Pharmacology, UCLA
Engineered antibodies have been developed for imaging carcinoembryonic antigen (CEA) in colon cancer, HER2 in breast cancer, CD20 in B-cell lymphoma and prostate stem cell antigen (PSCA) in prostate cancer. Recombinant antibody fragments such as diabodies (a dimer of single-chain Fv; 55 kDa), minibodies (dimer of scFv-CH3; 80 kDa), and scFv-Fc (dimer of scFv-CH2-CH3; 105 kDa) exhibit favorable characteristics for in vivo imaging, including rapid, specific localization to xenografts in mouse models and fast blood clearance. MicroPET imaging using fragments labeled with Iodine-124 (t1/2 = 4.2 d) and Copper-64 (t1/2 = 12.7 h) results in high contrast images. Factors influencing selection of the optimal fragment (including size, radiolabel, antigen internalization, etc.) will be discussed. Engineered antibodies recognizing cell surface targets represent a broad platform for developing novel imaging agents.
5:00 End of Imaging Week
