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2008 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report Research Interests The Laboratory of Noninvasive Imaging & Radiation Biology is devoted both to noninvasive imaging (i.e., depicting anatomic structures and physiology in living organisms without surgery) and to radiation biology (evaluating the consequences of external and internal radiation exposure in living organisms). The lab’s work follows three common themes: • Developing and using laboratory models that address medical imaging and radiation exposure problems • Advancing technology in imaging and radiation biology, including novel agents, probes, and reporters; new strategies for tackling research problems; and new instrumentation • Pursuing two-way translation between the laboratory and the clinical setting, i.e., using examples of human disease to design and improve laboratory model systems for study, as well as moving new discoveries from the laboratory benchtop to clinical use We depend heavily upon sophisticated instruments and equipment, including nuclear imaging cameras; planar and tomographic (3-D) X-ray units; clinical and research ultrasonography units; fluorescence detection systems; and cell and organism irradiation capability. Because of the equipment- and expertise-intensive nature of our projects, we could not succeed without the help of our valued collaborators. Our laboratory operates state-of-the-art noninvasive instruments for imaging mice, including a Vevo 770 high-resolution micro-ultrasound imaging system (VisualSonics) and a nanoSPECT/CT imaging unit (BioScan). We are pursuing two major collaborative projects in the area of radiation biology: • Nigel Crompton of Cornerstone University co-directs an effort to predict the sensitivity of a patient’s normal tissues to irradiation being administered for treatment of cancer. This project is made possible through collaboration with the radiation oncology service at Saint Mary’s Health Care and with the West Michigan Center for Family Health, both in Grand Rapids. For this project, a sample of the patient’s blood is drawn before radiation therapy. That blood sample is then irradiated under precise conditions of exposure, treated with fluorescent molecules that detect certain blood cells (lymphocytes), and analyzed by fluorescence-activated cell sorting (FACS) for evidence of lymphocyte death. We have also been investigating the effects of patient age, gender, and administered radiation dose on the lymphocyte response, and we are now working to determine the molecular basis for patient-to-patient variability. The midpoint results of our five-year clinical trial are being presented this year at the annual meeting of the American Society of Clinical Oncology. • In collaboration with Drs. Weiwen Deng, Aly Mageed, and Anthony Senagore of DeVos Children’s Hospital/ Spectrum Health, we are exploring a new approach for treating graft-versus-host disease in mice undergoing bone marrow transplantation, with planned extension to human patients in the near future. 30

VARI | 2008 Our major project in nuclear medicine is to develop and bring into clinical use radioactive antibodies and smaller molecules that attach to the Met receptor tyrosine kinase, collectively designated Met-avid radiopharmaceuticals (MARPs). Met plays a key role in causing cancers to become more aggressive, so that they spread to nearby tissues (invasion) and/or travel through the bloodstream or lymph channels to distant organs (metastasis). We previously showed that both large and small MARPs are useful for nuclear imaging of Met-expressing human tumors (xenografts) grown under the skin of immunodeficient mice. We are currently translating MARP-based imaging into mice with orthotopic xenografts (see below), as well as undertaking studies in additional animal species in order to gain governmental approval for the first MARP testing in humans. Finally, to support our internal and external collaborators, we operate a multimodality noninvasive imaging program for evaluating the growth, molecular expression, and response to therapy of aggressive human tumor xenografts grown subcutaneously or orthotopically in immunodeficient mice. Employing a combination of high-resolution ultrasound with and without contrast agents, planar and tomographic nuclear imaging, and CT imaging, we are studying tumors of the brain, adrenals, soft connective tissue, and bone. From studies using this imaging program, one paper (Ding et al. 2008) has been published; two manuscripts have been submitted for publication; and three more are being prepared. External Collaborators Our lab depends critically on intramural and extramural collaborations to address our research themes. Current extramural collaborators include scientists and physicians at the Department of Veterans Affairs Healthcare System and the University of Michigan Medical Center, both in Ann Arbor; Cornerstone University, West Michigan Heart, P.C., DeVos Children’s Hospital/ Spectrum Health, St. Mary’s Health Care, and West Michigan Center for Family Health, all in Grand Rapids; the University of Illinois in Champaign-Urbana; and VisualSonics, Inc., in Toronto. Recent Publications Gross, M.D., and R.V. Hay. In press. Molecular imaging of adrenal disease. Molecular Endocrinology. Ding, Yan, Elissa A. Boguslawski, Bree D. Berghuis, John J. Young, Zhongfa Zhang, Kim Hardy, Kyle Furge, Eric Kort, Arthur E. Frankel, Rick V. Hay, James H. Resau, and Nicholas S. Duesbery. 2008. Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma. Molecular Cancer Therapeutics 7(3): 648–658. Zhao, Ping, Tessa Grabinski, Chongfeng Gao, R. Scot Skinner, Troy Giambernardi, Yanli Su, Eric Hudson, James Resau, Milton Gross, George F. Vande Woude, Rick Hay, and Brian Cao. 2007. Identification of a Met-binding peptide from a phage display library. Clinical Cancer Research 13(20): 6049–6055. 31

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