In vivo Cancer Molecular Imaging Centers

NCI has awarded seven grants to support "In vivo Cancer Molecular Imaging Centers (ICMICs)". The ICMIC grants facilitate interaction among scientists from a variety of fields to conduct multidisciplinary research on cellular and molecular imaging related to cancer. The NCI is also supporting 12 Pre-ICMIC planning grants which provide time and funds for investigators and institutions to prepare themselves, organizationally and scientifically, to establish an ICMIC

Center for Molecular Imaging Research
Ralph Weissleder, M.D., Ph.D., Principal Investigator
Massachusetts General Hospital

Imaging sciences are at a stage at which in vivo imaging can occur at near micron resolutions with image specificity at the physiological, cellular and molecular level. Although the molecular basis of may diseases are well defined, we do not have a full understanding of the mechanism by which they develop in vivo nor have we fully harnessed the potential for translating advances in molecular science into clinical practice of imaging. Increased understanding of these areas and development of novel techniques is likely to provide new important directions in the earlier detection, molecular characterization and treatment of cancers.

The proposed program at the Center for Molecular Imaging Research (CMIR) at Massachusetts General Hospital (MGH), Harvard Medical School, is organized to attack fundamental imaging research at the cellular and molecular level. The principal research projects address imaging of specific enzymes in intact tumor environments using smart optical probes, in vivo imaging of angiogenesis and novel anti-angiogenic treatments, in vivo imaging of gene expression using new vectors and imaging marker genes, and in vivo tracking of progenitor and hematopoietic cells. These studies will be complemented by pilot projects dealing with viral delivery to tumors, developing high efficiency internalizing receptors for imaging probes, novel optical tomography systems for interrogating deep seated tumors and intracellular targeting and strategies for targeting of imaging probes to different intracellular compartments. The program also includes two scientific resources ( a chemistry resource for the synthesis of molecular imaging probes and a small animal imaging resource), a pilot project program and a career development program for multidisciplinary training of scientists. A major goal of the Center in the long-term is the multidisciplinary research approach and interaction with and involvement of basic science research groups in the Harvard and other national medical areas, largely through collaborative experiments utilizing the core resources. The Center will thus serve as a regional and national resource to move research in the field ahead and recruit new investigators into molecular imaging research.

MSKCC Center for Multidisciplinary In Vivo Molecular Imaging in Cancer
Ronald Blasberg, M.D., Principal Investigator
Memorial Sloan Kettering Cancer Center

With the advent of a better understanding of cell and biological processes at a molecular level coupled with the development of new biological reagents and probes, and recent developments and improvements in imaging technology, it is appropriate to focus attention on bringing together these advances. More importantly, it is recognized that molecular and cell-based imaging can impact directly on cancer treatment and diagnosis, and that the development and testing of new molecular-based therapies would benefit substantially from advances in our ability to image specific molecular and cell processes. In the last few years, several groups in this country (including several at MSKCC) have begun to integrate these diverse disciplines with some success. For example, multidisciplinary interactions at MSKCC has led to the demonstration of the feasibility for imaging transgene expression in vivo, and the use of noninvasive "reporter gene" imaging is being expanded to include specific cell processes at a molecular level. This theme, the translation and implementation of molecular and cell-based imaging into the clinical arena, is a strength of the MSKCC program and this proposal, and this theme is carried throughout the structure and individual components of this proposal.

The vision of this proposal, through the interaction of existing disciplines at MSKCC, is: 1) to develop noninvasive imaging paradigms that reflect specific cellular/molecular processes (such as endogenous gene expression) and protein-protein interactions within specific signal transduction pathways; 2) imaging the selective amplification of therapeutic genes; 3) monitoring the trafficking and targeting of genetically modified T cells; 4) imaging the growth and vascularization of tumor spheroids in vivo; 5) the use of NMR spectroscopy and PET imaging to optimize chemotherapy and gene therapy; 6) imaging the anti-tumor effects of ancamycins at a molecular and cellular level; 7) the application of metabolic PET imaging and molecular-pathology in the assessment of disease progression and response in patients with prostate cancer; 8) combining dosimetry estimates and imaging of molecular targeting with 86Y/90Y-labeled anti-CD19 and anti-CD20 antibodies in patients.

The coordinating theme of this proposal is the potential for molecular and cell-based imaging to have a direct impact on the treatment and diagnosis of cancer, and to provide new research opportunities that will further our understanding of cancer, cancer progression and response to therapies targeted to specific molecular processes

The UCLA Center for In vivo Imaging in Cancer Biology
Harvey Herschman, Ph.D., Principal Investigator
University of California – Los Angeles

UCLA has a mature biological imaging program based on PET instrumentation, chemistry, assays and applications, and a strong program in cancer biology, detection and treatment. Four years ago, Dr. Herschman, Director for Basic Research of the UCLA Comprehensive Cancer Center, and Dr. Phelps, Director for the UCLA PET Program, initiated a collaboration to merge the principles of cell and molecular biology with molecular imaging. With Drs. Barrio, Cherry, Gambhir, Sayamurthy and (later) Toyokuni, they initiated a program to monitor, in living animals, the expression of reporter genes in a non-invasive, repetitive and quantitative fashion. This collaboration developed two PET reporter genes, the dopamine D2 receptor and the Herpes Simplex Virus thymidine kinase, whose ectopic expression can be monitored in vivo by the PET reporter gene-dependent sequestration of systemically administered positron-labeled probes. The technology has been validated at UCLA both for virally delivered genes for gene therapy applications and in transgenic animal models for applications to repetitively monitoring gene expression.

The goal of the UCLA ICMIC is to translate new in vivo imaging technology to cancer research. Four outstanding investigators: Hong Wu, Charles Sawyers and Arnold Berk, along with our initial gene imaging group, are proposing projects that utilize microPET in living animals to answer questions in cancer initiation, progression, metastasis, vascularization, immune modulation and gene therapy that would otherwise be difficult to approach. Our Specialized Resources are designed to provide investigators not versed in imaging technologies with the most user-friendly access to positron-labeled probes, microPET scanning and data analysis. We think this initial outstanding cadre of recruits to imaging applications in cancer research will be catalytic, and draw additional faculty to this new technology through our ICMIC Developmental Funds Program. We also regard laboratory and didactic training at the interface of these disciplines, for both (I) new and established cancer investigators and (ii) new and established imaging researchers, as the major way to develop the next generation of cancer researchers - who will view this interface as seamless. Our Career Development Component will provide a collaborative laboratory environment and a tailored didactic program designed to merge these disciplines for individual trainees.

In Vivo Cellular and Molecular Imaging Center
Brian Ross, M.D., Principal Investigator
University of Michigan

The establishment of this In Vivo Cellular and Molecular Imaging Center (ICMIC) will provide for multidisciplinary interactions between scientists located at the Van Andel Institute and the University of Michigan. The ICMIC will provide the framework for channeling these interactions into fully developed and novel applications in the field of molecular imaging. These interactions, which have occurred during the P20 (Pre-ICMIC) funding stage, have already yielded some of the most creative and insightful ideas in this rapidly evolving area of research termed molecular imaging. This application seeks to build upon these successful scientific interactions and experimental results in order to provide for significant advances in oncologic imaging. This group of investigators has worked diligently to bring together a uniquely integrated approach using highly novel molecular imaging constructs and imaging approaches to “report” occurrences of key cellular and molecular events. These events include carcinogenesis (Project #2), apoptosis (Project #l), activation of oncogenes (Project #3), angiogenesis (Pilot Project #I) and metastasis (Pilot Project #2). Both the initial biological event and the subsequent measured biological response can be noninvasively monitored using magnetic resonance imaging and spectroscopy (WS), in vivo bioluminescence imaging (BLI) and positron emission tomography (PET). This multidisciplinary and multimodality approach will provide for a more complete understanding of the integrated events involved in the transformation process leading to tumor initiation, progression, angiogenesis, metastasis, immune response, and overall therapeutic response (or resistance). These studies will not only provide new imaging reagents and approaches for detection of these biological events, but ’ will also yield genetically engineered mice which will have reporter genes “built-in” for noninvasively and dynamically imaging these events in intact animals over time. As mentioned above, three Research Projects and two Pilot Projects have been developed along with a Career Development Program and three Cores. The Career Development Program provides a great opportunity to train and interact with young and enthusiastic investigators in the field of molecular imaging. The Administrative Core A provides administrative support including Internal and External Scientific review for all projects. The Small Animal Imaging Core B provides the necessary expertise and imaging services including microPET, MRI, microPET in uivo BLI, autoradiography, radiopharmaceutical synthesis and digital image processing. The Transgenic Animal Core C provides the necessary expertise and centralized resources for efficient production of novel and important genetically engineered mouse imaging models. This research proposal is a natural outgrowth of the progress made with current P20 and R24 NC1 support. Establishment of a world-leading ICMIC in Michigan is a priority and commitment made by the University of Michigan and the Van Andel Research Institute along with the State of Michigan (funds allocated through the Life Sciences Corridor) who have all contributed together with the NII-I in order to urovide the foundation necessary for ensurinp the success of this vital and intripuinp endeavor.

In Vivo Cellular and Molecular Imaging Center
David Piwnica-Worms, M.D., Principal Investigator
Washington University

Washington University Medical School's concept of an In Vivo Cellular and Molecular Imaging Center (ICMIC) envisions a process that will permit the Center to become the focal point for the development of novel in vivo molecular imaging initiatives on campus. This involves further expanding and reinforcing collaborations and enhancing the productivity of multidisciplinary programs in basic cancer cell biology and molecular imaging research. The ultimate objective of the proposed P50 Program is to combine the institutional expertise of Washington University in the basic sciences of molecular oncology, immunology, molecular genetics and signal transduction with our well developed infrastructure in medical imaging under the formal configuration of an ICMIC. We are strategically positioned to focus the majority of our ICMIC resources on the advancement of novel interactive and collaborative oncologic molecular imaging projects. To meet these goals, an organizational structure with three molecular imaging cores, four multidisciplinary ICMIC research projects, four developmental research projects, and educational program and a training/career development program are proposed. The four projects, representing innovative and exciting new initiatives on campus are:

1. In vivo Imaging of Gene Expression in Prostate Cancer,
2. Non-Invasive Monitoring of T Cell-Mediated Tumor Ablation
3. Imaging cancer Viruses with Tat Transducible Peptides
4. Imaging MDR1 P-glycoprotein Transport Activity In vivo with Tc-94m-Sestamibi PET to Predict Response to Chemotherapy in Extensive Stage Small Cell Lung Cancer

An organizational structure for an ICMIC has been established and all milestones achieved with our active P20 planning grant. The P50 Center grant will now promote excellence in molecular imaging in cancer research by providing a formal conduit for interdisciplinary multi-modality collaborations.

Molecular Imaging Center Planning
Grant
R. Edward Coleman, M.D., Principal Investigator
Duke University

The overall objective of this proposal is to develop a multidisciplinary research program for in vivo cellular and molecular imaging. Scientists from different schools at Duke University and departments in the medical center are working in specific areas of cancer research but no mechanism is available to provide interaction between these scientists. Although some of the scientists in the various schools and departments are starting to collaborate, this planning grant provides the focus to bring the separate scientific components together for performing the multidisciplinary research that will lead to new advances in in vivo cellular and molecular imaging.

The objectives of this planning grant are the following:

1. Develop and organizational structure that will stimulate and facilitate multidisciplinary research in the basic science and clinical application of new methods of imaging cancer.
2. Provide a forum to present new topics and to review multidisciplinary projects related to in vivo cellular and molecular imaging.
3. Select and monitor multidisciplinary development projects
4. Provide appropriate core facilities to support the development projects.

The goal of this planning grant is to develop the infrastructure, core facilities, and multidisciplinary interaction for submitting a P50 application for an in vivo and molecular imaging center.

Indiana ICMIC Planning Grant
Gary Hutchins, Ph.D., Principal Investigator
Indiana University

The goal of the Indiana-ICMIC planning grant is to foster collaboration between scientist involved in the development and application of in-vivo and in-vitro imaging methodologies with investigators involved in the extensive basic science and clinical cancer research programs of the Indiana University Cancer Center (IUCC). This pre-ICMIC planning grant program provides a unique opportunity to facilitate the integration of many currently disparate cancer research and imaging programs within our institution. While the overall goal of this program is to develop and apply non-invasive in-vivo imaging methods that are suitable for use in cancer patients, we feel that current state-of-the-art in vivo imaging techniques cannot provide all of the important information available through imaging technologies at the present time. Therefore, we have chosen an approach in which we will utilize both in vivo and in vitro imaging methods to aid in the study and development of cancer therapies. Our overall hypothesis is that in vivo imaging applications that elucidate unique physiologic mechanisms in neoplastic disease will serve as important surrogate markers for the presence of cancer and its response to therapy. The research specific aims of this program will be: 1) Identification and development of tracers and/or contrast agents to monitor gene expression and cellular physiology, 2) Development of novel in vitro and in vivo imaging methodologies for the study of cellular and molecular processes, and 3) Application of in vitro and in vivo imaging methods to monitor tumor cellular physiology and gene expression. The primary focus of this planning grant will be the development of 5-6 cancer imaging research programs that will form the basis of a comprehensive ICMIC application within the next 2-3 years.

JHU ICMIC PROGRAM
Zaver Bhujwalla, Ph.D., Principal Investigator
Johns Hopkins University

John Hopkins University: The twenty first century has witnessed an explosion of molecular biology techniques, amazing advances in imaging, and the design of unique imaging probes. Despite the tremendous strides made in these areas of science, the cure for cancer remains beyond our grasp. Cancer is a complex disease and the apparent impenetrability of the disease is largely due to the multiple, often redundant pathways, which appear to evolve through the genetic instability of cancer cells. The ability to identify and image key common pathways specific to cancer cells, and the ability to image the effectiveness and outcome of strategies designed against these targets is critically important in the treatment of this disease. The vision of our JHU ICMIC is to combine state-of-the-art imaging capabilities with powerful molecular biology techniques to define strategies with 'intent to cure'. In this proposal we have drawn upon our human resources at JHU to create a center consisting of a multidisciplinary group of premier individuals with diverse skills focused on translating molecular capabilities into imaging possibilities with the single purpose of understanding and curing cancer. Nearly all of the investigators participating in this ICMIC have interactive collaborative projects with one or more of the other investigators. The synergism generated by the collective skills of this unique group of individuals will lead to significant advances in the understanding of cancer and its treatment. The existing P20 program as well as the SAIRP have laid a strong foundation for the establishment of a world class in vivo cellular molecular imaging program at Johns Hopkins. The current proposal builds upon this strong foundation. Our JHU ICMIC structure consists of four interactive and closely related research components focused on hypoxia, HIF-1, and exploiting the hypoxia response element to target cancer cells through choline kinase inhibition. These research components are anchored by the participation of world renowned expertise in HIF-1. The research components will utilize MR, PET and Optical imaging technology to understand cancer vascularization, invasion and metastasis, to achieve effective cancer therapy. We have selected five developmental projects which are highly relevant to the goals of the ICMIC and interactive with the research components. Five resources devoted to adminstration, molecular biology, imaging, probes, and translational application will provide the infrastructure to support the research activities of the ICMIC. A career developmental program will train the future champions of molecular imaging in cancer. An advisory board consisting of the best scientists at Hopkins, and at several institutions in the US and abroad, will provide critical evaluation of the progress made. Strong institutional support and the advocacy of the Dean, Vice-Dean and Chairs of Radiology, Oncology and Biomedical Engineering will further ensure the success of the JHU ICMIC and fulfillment of its vision.

In vivo Multimodality Imaging of Neoplastic Disease
Christopher Contag, M.D., Principal Investigator
Stanford University

Toward the establishment of a multimodality molecular and cellular imaging center at Stanford University we have assembled a team of investigators comprised of leaders in the fields of imaging, molecular biology, oncology, chemistry and immunology; and have established research themes and programmatic cores that unify the common interests and expertise of these scientists. This team of investigators will be supported by an administrative core that will coordinate and direct the significant existing resources in MR, nuclear medicine, optical imaging, device development, gene delivery and small animal imaging. We are responding to NCI's RFA CA-99-002 for the P20 Planning Grant in coordination with this activity, and with the mission of developing a multimodality in vivo cellular and molecular imaging program for studying neoplastic disease. The program will address key issues in cancer from the level of gene expression and initiation of disease to cell death in response to novel therapeutic strategies. The specific aims that build this program are to:

1) maximize interaction among multidisciplinary investigators for a coordinated effort in cancer research and imaging,

2) develop an organizational structure to coordinate and manage the multidisciplinary programmatic cores and collaborative research effort,

3) identify a set of development projects that maximize the use of the core facilities and program strengths,

4) generate significant preliminary data with in the selected projects that contribute to our understanding of disease mechanisms and therapeutic intervention as well as advance novel imaging strategies.

These aims will be achieved by integrating the strengths of nine scientific cores - imaging, molecular biology, genetics, chemistry, biochemistry, drug delivery, computing/database & biostatistics, engineering and immunology. This will provide us with a unique opportunity for a multifaceted study of neoplasia that will identify novel therapeutic targets and reveal basic mechanisms of disease through state of the art imaging.

Center for In-vivo Molecular Functional Onco-Imaging
Orhan Nalcioglu, Ph.D., Principal Investigator
University of California – Irvine

We propose to establish an interdisciplinary functional onco-imaging pre-center where a broad spectrum of researchers including imaging scientists, microbiologists, chemists, clinical scientists among others will exchange ideas and collaborate with each other to advance the field of cancer research and clinical practice. The long-term objective of this partnership is to understand the initiation and progression of cancer through the development of image based measurement techniques and image contrast agents. The immediate objective for the In Vivo Molecular and Functional Onco-Imaging Pre-Center is to develop core technologies to be employed at the full center and build the necessary infrastructure for the successful implementation of the pilot research projects. Along with these, other immediate objectives include; 1) developing the necessary organizational structure, 2) disseminating the available technology and opportunities to the university researchers and clinicians via monthly colloquia, 3) establishing joint operation of core facilities when feasible, and 4) formulating the policies for project selection, funding, and monitoring.

Towards this goal we will focus on: 1. Integration of multi-modality equipment and techniques, 2. The initial modalities to be integrated are MR and Optical Imaging, 3. Using information obtained from such systems to understand the underlying mechanisms by analyzing the factors that contribute to bulk signal intensities, 4. Developing imaging agents to quantify tumor vascular properties with an ultimate goal of detecting angiogenesis, 6. Exploiting the above mentioned agents and image based measurement techniques to assess therapeutic efficacy, 7. Developing imaging/therapeutic agents to monitor therapy.

The initial scientific areas that would be participating at the center include image science (MR and optics), molecular biology, contrast agent development, immunohistochemistry, pathology, and oncology. As our track record indicates we already have had fairly strong collaborations among the initial members of the proposed center. What is in the present application is to form the necessary administrative structure as well as the infrastructure to elevate such collaborations to the next level to fulfill our vision in developing a molecular and Functional Onco-imaging Center to fight against cancer.

Center for Single Photo-Emitting Cancer Imaging Agents
Wynn Volkert, Ph.D., Principal Investigator
University of Missouri

The overall goal of the Center for Single Photon-Emitting Cancer Imaging Agents at the University of Missouri-Columbia (MU) is to foster interdisciplinary research to enable development of novel radiolabeled molecular imaging agents capable of selective in vivo uptake and retention in cancer cells. The Research Components and Development Projects supported by this grant are primarily focused on identification of single-photon emitting, site-directed in vivo targeting biomolecular-conjugates directed to cell surface receptors, antigens and angiogenesis markers with high specificity. Many of the bioconjugates developed in this ICMIC are designed to allow corresponding analogues labeled with particle-emitting radionuclides to be produced for potential radiotherapeutic applications. Molecular biology and biochemical techniques form the primary approach for the design and generation of new cancer targeting vectors, including in vivo phage display, combinatorial chemistry/biochemistry, and SPPS. The In vivo Cellular and Molecular Imaging Center (ICMIC) grant will provide essential support to maintain current and catalyze expansion of research teams which are composed of scientists that combine expertise in molecular biology, chemistry, radiopharmaceutical chemistry, comparative oncology, pharmacology, tumor biology and nuclear imaging. The major thrust of the research that will be conducted in the ICMIC will involve the development of 99mTc-, 111In-and 123I-labeled SPECT imaging agents. The radiolabeled bioconjugates to be designed and studied will selectively bind with high affinity to a variety of cancers, including breast, pancreatic, melanoma, lymphoma, prostate and lung cancers. Specialized Resources (Cores) supported by the ICMIC provide critical infrastructure and expertise to support cross-disciplinary research activities conducted in the Research Components and the Development Projects. The ICMIC will facilitate expansion and enhance the scope and quality of radiopharmaceutical sciences research related to development of novel, highly specific cancer targeting imaging agents. The scientific advances made in this program will foster new interdisciplinary research programs with other investigators at both this and extramural institutions, including other ICMICs and Pre-ICMICs.

Vanderbilt in vivo Imaging Center
David Piston, Ph.D., Principal Investigator
Vanderbilt University

The Vanderbilt In Vivo Imaging Center (VIVID) will focus on new optical and x-ray imaging modalities that have not yet been applied to cancer surveillance and management. Recent findings showing efficacy of anti-angiogenic approaches for cancer therapy emphasize the need for imaging modalities capable of evaluating tumor vascularity. Advances in laser scanning microscopy and fiber optics now permit true in vivo imaging, with resolution on the order of 100 nm. While application of optical methods may be minimally invasive, depending upon tissue sites, such procedures will deliver unprecedented speed and clarity. Furthermore, development of monochromatic X-ray imaging will provide resolutions below 30nm. Development projects will be focused around the role of angiogenesis in tumor development and metastasis. The convergence of Vanderbilt expertise in imaging methodologies with interests of Vanderbilt-Ingram Cancer Center investigators provides a unique opportunity. Ability to image molecules, such s VEGF, MMP's and COX-2, in tumors at diagnosis will permit rational design of therapies tailored to the individual tumor and patient.

Organizationally, core labs will be funded through direct collaborations with individual development projects, to maintain the focus on cancer diagnosis and treatment. Five core labs will be established based around existing facilities: 1) a mouse model core that will provide established mouse cancer models, as well as GFP transgenic and knock-in mice, 2) an in vitro imaging core that will support spectroscopy and microscopy, 3) an in vivo optical imaging core, that will use fiber-optic based and direct illumination modalities, 4) an monochromatic x-ray imaging core for in vivo morphological and molecular imaging, and finally 5) an MRI/Ultrasound/CT core that will be used to compare new methods with these accepted gold standards of in vivo imaging. These technologies span the range from cuvette to human subject. Collaborations between projects and cores promise to validate current hypotheses about tumor vascularization, and to rapidly apply these findings to clinical cancer diagnosis and therapy.

In Vivo Molecular and Microscopic Imaging of Cancer
James Willson, Principal Investigator
Case Western Reserve University

The in vivo molecular and microscopic imaging of cancer initiative at Case Western Reserve University (CWRU) and University Hospitals of Cleveland (UHC) will capitalize on extraordinary opportunities that advancements in imaging technologies offer for studying cancer noninvasively in animal models and in man. This initiative will build upon outstanding resources already in place at CWRU and UHC for in vivo imaging of cancer. Existing institutional strengths in the imaging sciences and cancer biology will be the foundation for establishing interactive teams of investigators from the imaging sciences, biochemistry, biomedical engineering, genetics, cancer biology, and chemistry, as well as investigators from the clinical disciplines. The goal will be to foster multidisciplinary research that will develop novel imaging techniques in live animal models to elucidate the consequences of altered gene expression and intracellular pathways involved in cancer etiology and treatment. The planning for this initiative has occurred over a two year period and already there exists impressive evidence of the powerful collaborations with the imaging sciences and cancer biologists that are possible on this campus. The leadership of this planning grant and the Comprehensive Cancer Center have been the impetus for this early development and will serve as the administrative base for launching the center and will foster close integration with existing imaging and cancer research programs. This initiative has strong institutional support and the active engagement of departmental leadership necessary to establish robust interdisciplinary research programs that will lead to further NCI sponsored research and become the basis for an NCI-funded center for in vivo cellular and molecular imaging in cancer.

In Vivo Cellular and Molecular Imaging Centers
Robert Mattrey, Principal Investigator
University of California - San Diego

Non-destructive cellular and molecular imaging of in vivo systems is critical to the understanding of basic molecular biologic processes involved in cancer. These imaging strategies are ideal for longitudinal studies that can assess the mechanism of action and the consequence of interventions and the monitoring of disease progression or regression in living animal. More importantly, these in vivo imaging tools can be translated to human patients. Because of the need to evaluate the efficacy of anti-angiogenesis agents using functional end-points, and because of the strong basic research program in this field at our institution, we have chosen angiogenesis as the principle focus for the proposed possible projects. This proposal offers 2 new ideas to molecular and cellular targeting. It introduces ultrasound imaging as a potentially powerful technique that can be applied worldwide as well as at the bedside and in the operating room. Because angiogenesis and apoptosis provide surface markers at the endothelial surface that are accessible to the vascular space and are therefore targetable by microbubble ultrasound contrast agents, we have proposed a potentially feasible study to test this hypothesis. This proposal also introduces the concept of targeted cellular killing by loading the imaging probe with a heavy metal rather than a positron or an MRI or an optical agent. In effect we can image and then kill the cells that are expressing a specific gene by optimal external radiation concentrates the energy in the cells of interest.

UCSD and the San Diego community including the Salk and Scripps institutes as well as other cancer research institutes and biotechnology companies, have broad expertise and substantial laboratory resources for basic cancer research. As an institution we have recruited a critical mass of imaging scientists and have committed resources to build a PET and MRI program. A PET center including a cyclotron will come on line by the end of 2000 and an MRI research facility with 4 high field systems 2 allowing human imaging will come on line in late 2001. This grant is timely and is exactly what is needed to create and foster interaction and collaboration among the investigators and to train and develop new talent in molecular biology with imaging expertise and imager with molecular biology expertise.

We have the commitment from the Director of the Cancer Center and the Dean to develop the Imaging Center into a comprehensive imaging program to qualify for the P50 grant in 2 years.

Molecular Imaging of Responses to Cancer Therapy
Michael Graham, M.D., Principal Investigator
University of Iowa

The goal of this ICMIC planning effort is to bring clinical oncologists, basic scientists, and imaging scientists together to develop new research collaborations. This will be through weekly seminars and monthly research retreats. These interdisciplinary collaborations are likely to lead to novel and significant advances in the use of imaging in caring for cancer patients. We intend to particularly emphasize the use of imaging in evaluating cancer therapy. Medical imaging, with X-rays, CT, MRI, PET, and nuclear medicine scans, has been used successfully for many years in diagnosing cancer. It has been used for evaluating therapy, but in a very unsophisticated way - simply determining if a tumor has increased or decreased in size. There are far more sensitive ways to determine tumor viability including measurements of blood flow, oxygenation, metabolism, and membrane integrity. There are also methods to evaluate delivery of drugs to tumors, by labeling with radioactive or magnetic tracers and imaging with PET or MRI. We intend to discuss and possibly study many of these approaches. Gene therapy is an area of specific focus. There is strong support for studies in this area and we plan to take advantage of the existing Gene Transfer Vector Core and Center for Gene Therapy of Cystic Fibrosis and Other Genetic Diseases that are active centers at the University of Iowa. There is strong institutional support for oncology research in general. University of Iowa recently was designated an NCI Cancer Center. This designation helps solidify and strengthen our commitment to cancer research. An unusual resource within the Department of Radiology is the section of Free Radical and Radiation biology. This is a strong research group with specific interest in using gene therapy. This interest has led to work with the iodine symporter gene as a report gene and the possibility of imaging it with a wider variety of iodine isotopes and iodine analogs. Three of the potential developmental projects are involved with this reporter gene: in validating its use in vivo, its use for tracking insertion of a gene for manganese superoxide dismutase, a free radical scavenger, and for tracking insertion and expression of p53 injected into tumors by sub-selective catheterization. We also intend to explore the use of novel heavy metal labels to follow viral vector delivery with MRI and CT. PET imaging of F18 flurothymidine will be used as a way to assess response to chemotherapy very early after treatment. Tumor glucose metabolism will be imaged to assess oxidative stress and as an indicator of tumor susceptibility to treatment.

Mid-Atlantic In vivo Cellular & Molecular Imaging Center
Jerry Glickson, Principal Investigator
University of Pennsylvania

An In vivo cellular and molecular imaging center (ICMIC) at the University of Pennsylvania will provide imaging resources and expertis to molecular biologists and clinicians engaged in research on molecular markers of cancer in small animal models and human subjects respectively. The imaging center, which will be called th Mid-Atlantic Molecular Imaging Center (MAMIC), will serve the greater Philadelphia area as well as a number of outstanding institutions throughout the world. Three imaging modalities will be employed, Nuclear Medicine (including PET and SPECT), NMR (including MRI and MRS), and Optical Imaging (focusing primarily on near infrared imaging, but also including redox scanning of ex vivo specimens). The proposed MAMIC will support a number of interdisciplinary highly interactive projects in three major research areas: 1) Tumor Biology, 2) Gene and Antiangiogenic Therapy, and 3) Radiation Oncology. Core facilities for Molecular Biology, Chemistry, Biostatistics and the three Imaging modalities are included. The proposal includes six potential developmental projects entitled: 1) Mechanism of apoptosis induction, 2) Peptidomimetic ligands of Her2/Neu receptors in breast cancer, 3) Targeting of LDL receptors on tumor cells, 4) Mechanism of extrogen/tamoxifen effects on Gd enhancement of breast tumor MR images, 5) treatment of colon tumor liver metastases by interferon transrection using creatine kinase as a marker gene, and 60 bacteriochlorophyll molecular beacons triggered by specific mRNAs. In addition to support for three developmental project, the MAMIC will provide core facilities, seminars and assistance in obtaining extramural funding to all the participants. Each of the Imaging Core Facilities will conduct research directed at development of imaging techniques that will enhnace the research programs of the participating scientific community. This imaging research will be supported by a Small Animal Imagin Grant that is in the process of being funded, and a Research Resource grant that has supported research in magnetic resonance and optical imaging for the past 15 years. The MAMIC will therefore serve as a catalyst and focal point for ongoing cancer research employing state of the art imaging techniques.

Development of a Cellular and Molecular-based Cancer Imaging Center
Peter Conti, Principal Investigator
University of Southern California

Over the last decade, medicine has undergone a profound and rapid change as a result of advances in cellular and molecular biology. Discoveries resulting from the sequencing of the human genome, advances in biotechnology and instrumentation, and a better understanding of tumor metabolism and physiology have contributed to this evolution as well. While we are rapidly approaching an understanding of the basic molecular mechanisms of cancer, our ability to image this disease at its earliest of stages, differentiate cell characteristics in vivo, and rationally monitor the effects of new therapies remains an unrealized goal.

Traditional anatomical imaging approaches in use today, such as radiography, CT and magnetic resonance imaging, play a fundamental role in clinical medicine, but do not provide the in vivo biochemical data needed to evaluate the metabolic and biochemical processes associated with cancer. Recent developments in magnetic resonance spectroscopy and positron emission tomography provide new dimensions to cancer imaging, offering unique ways to measure tumor biochemistry and the perturbations resulting from therapy. These technologies have not, however, realized their potential with respect to imaging the molecular basis of disease. This can only be achieved through integration of the advances made in several fields, including molecular and cellular biology, chemistry, physics, pharmacology, engineering and computer sciences.

The University of Southern California and the Norris Comprehensive Cancer Center have developed a proposal to design a molecular and cellular-based cancer Imaging Center. The concept of develop a USC/Norris Cancer Imaging Center has attracted productive teams of scientists committed to its successful implementation. Renowned experts in basic science and medicine are committed to creating the collaborative relationships necessary to achieve the ultimate goal of this initiative, which is to improve the care of cancer patients through translation of advances in cancer research to the clinical setting. We envision that the introduction of this NCI sponsored Cancer Imaging Center will foster the integration of advances in biomedical imaging and basic science, leading to improvements in diagnosis and staging of cancer, guidance of therapy, and monitoring of treatment by providing more useful and relevant physiological and biochemical information than is available today.

The University and Norris Cancer Center are committed to development of the USC Cancer Imaging Center. As noted in the proposal, the Cancer Center is making a substantial financial committeemen to the proposed Imaging Center, including partial funding of a Post-doctoral Research Fellow, and matching pilot/project funding.

Southwest In Vivo Cellular and Molecular Imaging Center
Ralph Mason, Principal Investigator
University of Texas Southwestern

The Southwestern In Vivo Cancer Cellular and Molecular Imaging Center will develop new procedures for non-invasively identifying cancer, predicting therapeutic efficacy, and assessing response to therapy encompassing both MR and nuclear techniques. There is an increasing sentiment that therapy should be individualized to the characteristics of each patient's tumor (disease) taking into account genetic and epigenetic (micro-environmental) factors. While single parameters have often been the focus of modulated treatment (e.g., hypoxia), it is increasingly evident that a multi-parametric, multi-disciplinary approach is required.

We focus on four major Research Areas, capitalizing on the strengths of UT Southwestern: 1) Prognostic Radiology: development and evaluation of physiological molecular markers of response to therapy (e.g., p)2, pH and blood flow); 2) Genetic Signatures: development of non-invasive molecular markers to image disease progression (array technology to identify characteristic over or under expression of genes); 3) Instrumentation and Assays: development and application of non-invasive methods for assessing pharmacokinetics and pharmacodynamics of therapeutic interventions non-invasively (small animal nuclear imaging instruments and novel MR active reporter molecules); 4 Molecules and Mechanics: development and application of novel molecular and cellular tumor targeting strategies (identification of bioactive ligands and delivery using ultrasonic stimulation).

Interactions stimulated by the Pre-ICMIC among leading investigators [physicians (oncologists, radiologists), basic scientists (physicists, molecular biologists, tumor biologists, chemists), and imaging scientists (engineers, physicists, chemists)] are already generating novel results, pointing to exciting new research leads and clinical practice. Facilities will be made available to outstanding development. Projects based on competitive review to generate new collaborative research programs in oncology. We believe imaging will lead to more efficient and rapid development of novel therapies (e.g., tumor directed infarcts and gene therapy) by providing assays of agent distribution and activity and tumor response. Ultimately, early indicators of therapeutic efficacy will improve cure, reduce unnecessary medication (yielding cost saving), and above all, improve survival and quality of life for patients. Thus we foresee development from the bench to the bedside, and viewbox, with iterative loops to refine the utility of cancer imaging.

Wisconsin Interdisciplinary Molecular Imaging Center
Tom Grist, Principal Investigator
University of Wisconsin - Madison

The University of Wisconsin is unique in that two federally funded Cancer Centers, The UW Comprehensive Cancer Center, and the McArdle Laboratory for Cancer Research are both located on campus. These two centers are now in the process of merging to form a single comprehensive cancer center with tremendous cancer biology and clinical intellectual and technical resources. In conjunction with this merger, the University recently unveiled its HealthStar-2000 initiative, one facet of which includes building a new 350,000ft2 twin-tower medical research facility to be known as the Interdisciplinary Research Complex (IRC). The IRC will be strategically located adjacent to the current UW Hospital and Comprehensive Cancer Center complex and equidistant from both the Waisman center and New School of Pharmacy building (completion in 2000).

The IRC will house cancer, heart and vascular, molecular medicine, neuroscience, transplantation, aging and women's health programs. The IRC is intended to catalyze and nurture interdisciplinary research. A strong emphasis will be placed on research with a molecular theme. Indeed, molecular biology applied in translational research will serve as the intellectual theme of the IRC. Moreover, the new IRC will house a 50,000 ft2 Imaging Science Center where collaborating medical physicists, radiologists, oncologists, and cardiologists will develop noninvasive diagnostic technologies. Therefore, the long term objective of this P20 pre-molecular imaging center planning grant, nicknamed the Wisconsin Interdisciplinary Molecular Imaging Center (WIMIC), is to form the foundation of a subsequent P50 interdisciplinary molecular imaging center grant in order to meld the vast cancer research and imaging sciences community at UW into a leading interdisciplinary molecular imaging center.

The specific objectives of this proposal are to: 1) Organize a structure to encourage and foster the interaction of basic cancer biology researchers with imaging scientists in an effort to answer unique cancer-related questions. 2) To provide scientists access to novel targeted cell-selective imaging agents and to evaluate these agents in new biological systems. 3) To utilize shared institutional funds to provide funding for interdisciplinary post doctoral and graduate student support. 4) Initiate a bimonthly seminar series featuring elite molecular imaging scientists and state of the art imaging technologies and open to scientists of all disciplines. 5) Provide opportunities for women, minority, and young investigators through interaction with WIMIC members and small seed grants.

Last Updated: August 2002