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Current SAIRP Project Abstracts

• University of Michigan
• University of Arizona
• University of Pennsylvania
• Memorial Sloan Kettering
• Washington University
• Duke University
• Johns Hopkins University
• Massachusetts General Hospital
• Stanford University
• University of California, LA

University of Michigan

There has been a dramatic increase in interest in noninvasive imaging of small animal tumor models at the University of Michigan over the past several years. In order to assist investigators with imaging requirements, a Magnetic Resonance Imaging (MRI) and Digital Image Processing Laboratory (DIPL) were developed as part of the University of Michigan Comprehensive Cancer Center Core Facilities. The MRI and DIPL core labs are currently available to assist a limited number of investigators with acquisition of imaging data and post processing. The interest in this technology has outgrown both the capabilities of the equipment as well as the number of laboratory personnel. The objectives of this proposal are to: 1)Update and expand the capabilities of our 2T, 7T and 9.4T horizontal bore animal MR imaging and spectroscopy systems (MRI/S) including adding microimaging capabilities for high-resolution mouse imaging. 2) Acquire a miniature x-ray computed tomography (CT) device capable of scanning both mice and rats. 3) Provide the capability to obtain quantitative autoradiographic data of tumors for correlation and comparison with MRI/S, CT and MicroPET data. 4) Increase the number of personnel available to assist investigators with these technologies. 5) Develop and implement new imaging and post processing capabilities to enhance the quantitative analysis of imaging data. These objectives were defined to bring the University of Michigan small animal especially important since our current user base encompasses many faculty at the University of Michigan and other academic institutions in Michigan, Wisconsin, Minnesota, as well as an investigator at a local company with NIH SBIR funding for cancer research. The overall goal of this proposal will be to provide a shared resource to improve the tool that cancer researchers can utilize to pursue their individual research interests. Significantly improving the capabilities and throughput of our imaging facilitate will give more investigators access to these technologies and will provide a more diverse and dynamic exchange of techniques and ideas. This type of interaction will surely foster interdisciplinary collaborations in cancer research.

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University of Arizona

The University of Arizona Health Sciences Center and the Arizona Comprehensive Cancer Center propose to establish the Southwest Animal Imaging Resource (SWAIR). The purpose of the SWAIR is to provide the cancer research community access to state-of-the-art in vivo imaging based on magnetic resonance (MR), single photon emission computed tomography (SPECT) and optical coherence tomography (OCT). The integrated program will also provide common access to essential cores for veterinary anesthesia and computing/electrical engineering. The major purpose of the SWAIR will be to provide state-of-the-art imaging access to the base grants. Eight cancer-related research programs form the original cohort of base grants. These represent diverse aspects of cancer research, from basic cellular and molecular mechanisms, to diagnosis, to monitoring and improving therapeutic response. The program will support continuing research to improve the application of the imaging modalities to cancer biology in vivo. MR research will continue to improve methods for spectral imaging (MRSI), high resolution morphometry, motion-insensitive diffusion imaging, pH imaging, and analyses of Gadolinium-enhanced dynamic contrast. These techniques will be applied and developed on newly upgraded 4.7 and 9.4 Tesla instruments. SPECT research will involve construction of a state-of-the-art high-resolution FASTSPECT system, which will be dedicated to animal imaging. Research will focus on improved detectors, readout electronics, and system characterization. The latter is essential for optimizing the spatial resolution of the SPECT system. In the OCT program, a dedicated instrument will be constructed and applied non-invasively to image skin lesions in experimental animals. Research will continue to improve the applicability of this relatively new technology to the diagnosis and serial monitoring of epidermal and epithelial lesions in vivo. Research will also be conducted in the veterinary anesthesia core to continue to improve anesthesia formulations that do not interfere with the physiology being measured. This is an important issue since these modern imaging techniques monitor functional properties of tumors, which can be perturbed in the anesthetized state. The electrical/computing core will help with the construction and maintenance of the imaging instruments. It will also provide support the general computing resources of the entire program.

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University of Pennsylvania

Creation of a Small Animal Imaging Resource Program (SAIRP) at the University of Pennsylvania supporting research by investigators at this institution and also at the Fox Chase Cancer Center and Thomas Jefferson University is proposed. This SAIRP will provide three imaging modalities -- 1) Magnetic Resonance Imaging and Spectroscopy MRI/S). 2) optical imaging covering the ultraviolet through near infrared (UV-NIR), and positron emission tomography (PET). The MRI/S facilities are now in place; the UV-NIR and PET facilities are now operational on the scale of human patients and will be adapted to studies of small animals (mice and rats) by the end of the first year. The SAIRP will support the research of 13 NIH funded projects dealing with 1) modification of tumor response to radiation and hyperthermia, 2) methods of monitoring tumor hypoxia, 3) gene therapy of brain tumors, 4) immunotherapy of tumors, 5) detection of breast cancer and 6) detection of tumor response to chemotherapy and radiation therapy. Ancillary facilities for redox scanning, NIR time resolved spectroscopy, electronics, animal management, synthesis of contrast agent and physiological probes, histology, computer resources, biostatistics and MR of perfused cells will be provided. Research and development and D) projects will be directed towards the development of novel NMR capabilities that will enhance the research capabilities of the base projects. These R and D projects are: A. MRI of Small Animal Tumors, including: A1. Small Animal Microimaging. A2. Functional Imaging of Tumors, B. Multinuclear Spectroscopy, including: B1. Chemical Shift Selective MR Imaging of 31P in Animal Tumors, B2. 1H{17O} MRI of Tumors, B3. In Vivo Imaging of Intra- and Extracellular Na+ and pH in Tumors, and C. NMR Techniques for Monitoring Gene Therapy of Brain Tumors.

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Memorial Sloan Kettering

Research at Memorial Sloan Kettering Cancer Center is focused on cancer diagnosis and enhancing responses of tumor to treatment with a goal of curing cancer. Animal studies of novel cancer therapeutics, while imperfect as a treatment model, have utility, both in studying therapeutic efficacy and toxicity. Because tumors are heterogenous, both between individuals and within a single tumor, non-invasive imaging studies are necessary to provide information about variation in response. We propose to use three imaging technologies, nuclear magnetic resonance (NMR), positron emission tomography (PET), and quantitative autoradiography (QAR) to study a diverse range of topics that relate to cancer treatment. The three imaging techniques chosen were based on the fact that they are closely related. PET and QAR studies are synergistic, since QAR can be used to screen and evaluate new compounds that may be potential radiopharmaceuticals for PET. QAR and NMR both can evaluate blood flow and vascular permeability. PET and NMR can be used to investigate tumor metabolism, and clinically are often used in a complementary manner. The range of projects studied include predicting tumor response to treatment, dosimetry for radioimmunotherapy, pharmacology, gene therapy, tumor metabolism, and evaluating responses to novel cytostatic agents. In particular, we have focused on novel treatments, such as gene therapy, new "designer" drugs that are undergoing early clinical trials but lack endpoints since they are cytostatic. An important component of this research effort is in the imaging development effort. NMR studies will focus on designing better radiofrequency probes, enhancing spectral resolution, quantitation and image processing. PET research focuses on modeling, particularly of radiolabeled monoclonal antibodies, image processing and spatial registration. Dr. Blasberg will extend his previous novel developments in QAR and use 4 isotopes to study 4 different physiologic or biochemical processes within a tumor concurrently. Leadership will come from the imaging scientists (Drs. Koutcher, Blasberg and Larson) and also from the molecular pharmacology group. Monthly meetings between these two groups are viewed as essential to decide which problems are important and appropriate to be addressed by imaging technology. A Technology Committee also evaluate new imaging technologies for consideration.

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Washington University

It is proposed to establish the Washington University Small Animal Imaging Resource (WUSAIR) to provide state-of-the-art facilities and infrastructure for magnetic resonance imaging (MRI) and positron emission tomography (PET) analysis of mice, rats and other small laboratory animals. Located in the heart of Washington University Medical Center in St. Louis, WUSAIR will combine instrumental and intellectual capabilities found at few other institutions. WUSAIR will serve a broad community of scientists non-expert in MRI or PET technology who have a pressing need for quantitative image analysis of small laboratory animal model systems. A particular focus will be on mice and rat models of cancer. WUSAIR will also continue research and development at the frontier of imaging technology in an effort to make the most powerful of the new imaging strategies available to its community of users. Purchase of new PET and/or MRI scanners is not requested herein. Indeed, Washington University has generously supported the recent acquisition of such equipment as part of its continuing and substantive commitment to basic biomedical research. Currently on site and fully operation in the Imaging Research Center are two Varian INOVA 4.7 T MRI/MRS small animal research scanners. A PET scanner dedicated to small animal research, the microPET, will be delivered and sited in the Clinical Sciences Research Building early next year. These PET and MRI small animal research scanners will form the core instrumentation of WUSAIR.

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Duke University

We propose the formation of the Duke University Molecular Imaging Center (DUMIC) consisting of a consortium of cancer researchers and imaging scientists. The goals of the program are to a) develop the integrated technologies required for multi-modality molecular imaging in small animals, b) apply these technologies to important basic questions in cancer research, c) effectively disseminate the technologies, and d) train the next generation of technologists and scientists in the use of these technologies. More specifically, we will provide an infrastructure to allow cancer researchers at Duke to exploit and integrate the following imaging resources: l) In vivo magnetic resonance microscopy to 50 x 50 x 50 microns (1.25 x 10-4 mm3) and magnetic resonance histology to 10 x 10 x 10 microns (1 x 10-6 mm3), 2) X-ray microscopy to 20 x 20 microns @ 10 ms temporal resolution, 3) Optical imaging for detection of luciferase reporter gene expression in vivo with sensitivity down to 1000 cells and spatial resolution down to 50 microns, 4) microPET to spatial resolution of less than or equal to 2 x 2 x 2 millimeters, 5) State-of-the-art animal support with real-time physiologic monitoring, 6) A unified image analysis environment to facilitate integration of imaging studies.

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Johns Hopkins University

The goal of this application is to expand our interdisciplinary small animal imaging program to include complementary imaging capabilities that will increase our understanding of cancer. MR-based functional and metabolic imaging is the backbone of our current effort, which has been formalized into the Johns Hopkins pre-ICMIC. We now intend to balance that effort with a program that incorporates a strong nuclear imaging component. We intend to obtain a dedicated small animal PET device and undertake the development of a biplane x-ray/gamma scintigraphy system that will enable us to study a wider array of physiologic processes. We are also initiating a collaboration to enhance our optical imaging potential. We intend to focus on three broad areas relevant to the diagnosis and treatment of cancer: new technology development, including drug development, in-depth analysis of the tumor microenvironment, and quantification of gene expression, primarily in cells and tissues expressing the malignant phenotype. We will pursue these aims by coordinating efforts in 3 core resource facilities: (I) technology development, (II) molecular biology and (III) chemistry, all of which will support the central imaging core. A quantitative subcore will also support the imaging core. Among the 12 base grants are one center grant (the pre-ICMIC) and 3 program project grants, all of which address important questions in cancer biology and/or therapy and will be greatly enhanced by an imaging component. The combined expertise of Johns Hopkins University (JHU), the University of Virginia and the NIH will create an SAIRP with strong molecular imaging capabilities accessible to researchers in the Mid-Atlantic region.

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Massachusetts General Hospital

Small animal models, particularly mice (Inbred, immunodeficient, otherwise genetically engineered), are increasingly recognized as powerful tools in cancer research. There has been a dramatic increase in interest in noninvasive imaging of small animal tumor models at Harvard and MIT over the past several years. The Center for Molecular Imaging Research (CMIR) at MGH has been a leader in small animal imaging technology development and has assisted a limited number of investigators with image acquisition and post processing. The interest in mouse imaging has far outgrown the availability of imaging equipment as well as the number of laboratory personnel. The proposed Small Animal Imaging Resource Program (SAIRP) at the MGH-CMIR, is organized to 1) implement new high resolution imaging capabilities for mice and rats, 2) perform technology development to further improve in vivo detection technology and 3) provide a forum for training in handling and imaging of small laboratory animals. These objectives were defined to bring the dedicated small animal imaging facility up to the state-of-the-art in order to increase its efficiency and accessibility for users in the New England area. The Resource currently serves 7 funded base grants, 4 pending grants and 3 developmental grants, from different institutions. Technology development will be directed towards optimizing and adapting new imaging technologies, validating new imaging approaches, and correlating structural and functional information. Some of the mechanisms to enhance synergy, interaction and wider spread usage of this resource include 1) an interactive website for on-line sign-up and access for data download, 2) monthly seminars in small animal imaging, 3) dissemination of resource availability through lectures and publications, 4) pilot grants to attract novel projects and new users and 5) creating a quarantine/holding facility to handle animals from other institutions. The overall goal of this application will be to provide a shared resource for the New England region open to cancer researchers and in particular the two local mouse model consortia to pursue their individual research interests. Significantly improving the capabilities and throughput of our imaging facilities will give more investigators access to these technologies and will provide a more diverse and dynamic exchange of techniques and ideas. This type of interaction is expected to foster productive interdisciplinary collaborations in cancer research.

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Stanford University

In vivo imaging of neoplastic disease at early stages or as residual disease after therapy is difficult due to relatively low cell numbers, weak signals and previously insensitive detection methods. At late stages, functional changes are relevant to treatment but have been difficult to discern in vivo. In an interdisciplinary approach, the here assembled consortium of investigators will address these obstacles through the use of novel optical imaging strategies, and improvements to the more conventional imaging modalities of MRI, CT and SPECT. These will permit us to address questions pertaining to the genetics, physiology and therapy of neoplastic disease by monitoring both structural and functional changes in small animal models of cancer noninvasively and in real-time. The optical imaging system, developed by investigators in this core resource program, uses cells labeled with the genetic reporters, such as luciferase, which encode photoproteins that emit light which is detectable by highly-sensitive CCD-cameras from outside the animal's body. This enables us to observe as few as a thousand cells and perform in viva functional analyses. As such, examination of the cells' response to drugs and physiological stimuli can be assessed. State of the art MR imaging will be employed in conjunction with the optical methods, and in parallel, to complement and strengthen the analyses. To enhance detection sensitivity and resolution, engineering faculty will develop new adaptations to MRI, including a novel prepolarized system, to increase versatility. New micro-CT and micro-SPECT systems will be deployed for structural analyses and molecular detection, respectively, in animal models. We will modify reporter genes and contrast agents, assess gene expression in transgenic animals, determine the role of specific genes in the development and control of cancer, optimize optical detectors and apply state of the art MRI methods to small animal models. Furthermore, this multiple modality approach enables us to evaluate the efficacy of combination drug therapies and novel immune cell therapies in treating various types of tumor cells at different disease stages. The specific aims of this application are aimed at increasing the capabilities of investigators in the molecular and cellular in vivo study of cancer, develop improved imaging technologies that push the limits of current bioimaging methods, introduce young investigators to state of the art imaging, and accelerate the in vivo quantitative evaluation of novel antineoplastic therapeutics. These goals will be met by generating a shared imaging research resource at Stanford University with the ability of spatiotemporal analyses of both structure and function in neoplastic disease models.

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University of California, LA

UCLA has a mature small animal imaging program based on digital whole body autoradiography (DWBA) and micro positron emission tomography (microPET). We have significant investments in the study of small animal cancer models using PET reporter gene technology. Reporter genes in combination with DWBA and microPET have provided us the ability to study cancer biology, cell trafficking, and pre-clinical models for gene therapy. It is through these studies that we have better understood the limitations of our current technologies and therefore propose the acquisition of micro computed tomography (microCAT) and optical charge coupled device (CCD) imaging systems. We will also acquire a critically needed computer server and data archiving system for the large amounts of data generated through this work. We will initially allow six seasoned cancer investigators to use the resource and then grow by adding up to three investigators per year. MicroCAT will allow us to image the underlying anatomy in our mouse cancer models. This will be critical in helping us to understand the location(s) of various cellular events without the need to sacrifice the animals. Furthermore through direct research proposed in this work we will register the microPET and microCAT information to provide our researchers with maximal information on function and anatomy. The optical CCD system will also be critical in helping to accelerate our cancer related research. The use of the firefly luciferase (FLUC) reporter gene will allow us to more rapidly study small animal models without radioactive probes. This system has the capability of imaging low levels of light from within a living small animal. We will use reporter systems that couple FLUC and PET reporter genes in order to have the flexibility to image in either an optical CCD system or the microPET. This will help to accelerate the development of various models that are dependent on reporter gene technology. Quantitation of data from all modalities will always be stressed throughout the SAIRP. We will also develop a strong training program that will help investigators and their students to become independent and confident in using the available resources. Use of the entire resource will be coordinated by intemet based scheduling software and an oversight committee. We are confident that the new resources with microCAT and optical CCD technologies will help to provide UCLA investigators with state-of-art tools for non-invasively imaging mouse cancer models.

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Last Updated: April 2004