John Hopkins University ¹
Zaver Bhujwalla, PI

Massachusetts General Hospital ²
Ralph Weissleder, PI

Memorial Sloan Kettering Cancer Center ³
Ron Blasberg, PI

University of California, Los Angeles ⁴
Harvey Herschman, PI

University of Michigan ⁵
Brian Ross, PI

University of Missouri ⁶
Wynn Volkert, PI

Washington University ⁷
David Piwnica-Worms, PI

Stanford University ⁸
Sanjiv Gambhir, M.D.

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 has 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 administration, 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.

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 vivo 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 provide the foundation necessary for ensuring the success of this vital and intriguing endeavor.

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.

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.

In vivo and Molecular Imaging Center at Stanford
Sanjiv Gambhir, M.D.
Stanford University

Stanford University has a rapidly expanding program for the molecular imaging of living subjects. Through significant investments by the University in new space, infrastructure, and new faculty recruitments the Molecular Imaging Program at Stanford (MIPS) was established. Dr. Sam Gambhir, Professor of Radiology and Bioengineering was recruited and appointed by the Dean of the Medical School as Director of the MIPS. He works closely with Dr. Christopher Contag, Associate Professor of Pediatrics and of Microbiology and Immunology, Co-Director of the MIPS. Together, Drs. Gambhir (Principal Investigator for this grant application) and Contag (Co-Principal Investigator) form a unique leadership team that spans the breadth of disciplines involved in multimodality molecular imaging.

The MIPS is highly supported by the Deans of Medicine, Engineering, and Humanities & Sciences, Chairs of Radiology, Radiation Oncology, Bioengineering and other senior faculty who win also serve on the internal advisory board for this grant application. The in vivo cellular and molecular imaging center at Stanford (ICMIC at Stanford) continues the momentum that built the MIPS. The goal of the ICMIC at Stanford is to provide better links between pre-clinical models of cancer and the clinical management of cancer patients by novel research in multimodality molecular imaging. Four research projects focused on pre-clinical small animal cancer models that utilize multimodality molecular imaging to understand basic cancer biology and optimize novel cancer therapies, and four developmental projects spanning different components of the molecular imaging research chain are the main science driving this grant.

Investigators from a variety of disciplines and expertise including Dr. Felsher-Medical Oncology, Dr. Chen-Radiochemistry, Dr. Rao-Chemistry, Dr. Schnitzer-Applied Physics, Dr. Boyer-Radiation Oncology, Dr. Blankenberg-Radiology, Dr. Levin-Medical Physics, Dr. Nolan-Cell & Molecular Biology, Dr. PlevritIs-Mathematical Modeling, and Dr. Napel-lmage Visualization are all committed to advancing the science of molecular imaging and to this research application in particular. Four specialized resources including 1-Chemistry/Radiochemistry, 2- Flow Cytometry, 3- Small Animal Imaging and 4- Quantitation & Visualization help insure that the ICMIC at Stanford functions efficiently. Finally, a structured training program with 2 post-docs funded by the ICMIC at Stanford and 2 additional post-docs funded through matching funds from Stanford insure the ability to train next-generation interdisciplinary leaders in molecular imaging. Stanford University, with support for this grant from the NCI, is poised to be a major contributor to the research and training efforts for the rapidly growing field of molecular imaging.

Web page: http://mips.stanford.edu