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2004 Scientific Report

ages of 15 and 35.

ages of 15 and 35. Previously, Bin collaborated with Indiana University’s Dr. Larry Einhorn, one of our previous Nathans Award recipients, on a study to determine why 10% of testicular cancer patients are resistant to treatment for the disease. Through this research the scientists identified a set of genes that distinguishes between testicular cancer patients who relapse during the early stages of therapy and those who relapse two or more years after their initial treatment. The latter group is resistant to chemotherapy. The new study could allow the identification of the underlying mechanisms for chemoresistance in those patients so that additional intervention measures may be applied. In a new study on prostate cancer, our scientists hope to gain a clearer understanding of what makes this disease spread. Led by Cindy Miranti, the goal of this project is to determine what happens to prostate tumor cells when two known metastatic suppressor genes stop functioning. Funded by a three-year grant from the Department of Defense, the research will allow Cindy and her Laboratory of Integrin Signaling and Tumorigenesis to better understand how the loss of function in these genes leads to increased metastasis. Currently, metastatic prostate cancer is not treatable. Cindy’s research aims to identify new and effective therapies that will ultimately save lives. The Department of Defense also funded a three-year grant for Bart Williams to test the hypothesis that alterations in β-catenin regulation directly contribute to prostate cancer progression and the propensity of prostate cancer to metastasize to the bone. Members of Bart’s laboratory, in collaboration with Dr. Wade Bushman at the University of Wisconsin, have created a mouse model in which up-regulation of β-catenin leads to the development of early-onset prostate cancer. Their current work is aimed at examining the androgen dependence of these tumors, their capacity to metastasize, and the genetic interaction of changes in Wnt signaling with other genetic changes observed in prostate cancer. Additional awards, including postdoctoral fellowships, have come from many other funding organizations, such as the Elsa U. Pardee Foundation, the Wenner-Gren Foundation, the March of Dimes, the American Cancer Society, the National Cancer Center, the National Osteoporosis Foundation, the Life Sciences Research Foundation, the American Brain Tumor Foundation, the Gerber Foundation, and the Multiple Myeloma Research Foundation. During the past year Nick Duesbery has extended studies on the discovery that anthrax tumor lethal factor (TLF) has potential as an antitumor agent in the treatment of not only melanoma (studies with Han- Mo Koo) but also certain sarcomas. This has opened new avenues for investigation and has led to a collaboration with Dr. Art Frankel and a partnership with Wake Forest University Medical School to produce TLF of a pharmaceutical grade suitable for preclinical studies and potential testing in humans. By spring of 2005 there should be a significant stock of TLF for testing. Craig Webb is establishing a dedicated multiple myeloma laboratory at VARI. This new research effort will use integrated genomic and proteomic capabilities developed within the laboratory to study the molecular causes of multiple myeloma. Current work centers on identifying the genes and proteins that can predict the response of myeloma patients to existing therapies, as well as to identify novel treatments for the disease. The goals are to develop tests that accurately diagnose the disease in its earliest stages and identify the optimal treatments for patients with multiple myeloma. This research is being conducted in collaboration with several oncologists/hematologists from Grand Rapids, Detroit, and Toronto. The multiple myeloma lab is being supported in part through generous contributions from the McCarty Foundation and a fellowship to Jennifer Bromberg-White from the Multiple Myeloma Research Foundation. Brian Cao (Laboratory of Antibody Technology) and Rick Hay (Laboratory for Molecular Oncology) have collaborated in the development of two radiolabeled monoclonal antibodies to the Met receptor molecule for nuclear imaging studies. We are currently using these radiolabeled antibodies in animal models of human and canine prostate cancer. These antibodies could potentially be used for radioimmunotherapeutic applications as well. Both Greg Cavey and Eric Xu, the most recent appointments to our staff, have their labo- 4

atories in full operation. Greg (Laboratory of Mass Spectrometry and Proteomics) is supporting a number of the VARI labs with Q-tof (quadrupole-time of flight) mass spectrometry for many types of proteomic studies. Two additional instruments, a second Q-tof and an ion trap mass spectrometer, are soon to be operational. Eric’s Laboratory of Structural Sciences is busy with studies of nuclear hormone receptors and the Met tyrosine kinase receptor, two different classes of proteins that have been proven to be important therapeutic targets for cancer and metabolic diseases. The lab has generated crystals of a number of nuclear hormone receptors and of fragments of hepatocyte growth factor (a Met receptor ligand). They are using the Advanced Photon Source (APS) at Argonne National Laboratory near Chicago to obtain high-resolution diffractions from these crystals. Together with Michigan State University, the University of Michigan, and Northwestern University, VARI was a founding member of the Life Sciences Collaborative Access Team that operates the APS Sector 21. We continue to actively integrate into the Grand Rapids medical community as part of our commitment to translation of our research into clinical practice. We are now a member of the Michigan Cancer Consortium (MCC), a partnership of 75 public, private, and voluntary organizations committed to reducing the human and economic impact of cancer in Michigan. MCC was formed and its priorities developed as a focused, coordinated initiative among member organizations that will collectively have an impact far greater than individual efforts. One MCC priority is to increase the number and diversity of participants enrolled in clinical cancer research. In 2003 we established the Tumor Tissue Donation Program. Through an informational effort directed at the lay public and collaborating healthcare providers, we emphasized the crucial importance of fresh tumor tissue samples to our studies, which aim to determine the causes of cancer, how to prevent it, and how to treat it. We have asked area physicians and hospitals to seek consent from patients undergoing cancer surgery so that we may obtain tumor tissue left over from the surgery for research use. This program, under the direction of Rick Hay, our Deputy Director for Clinical Programs, has been very well received by the community. We have partnered with the DeVos Children’s Hospital in Grand Rapids in a funded pediatric training fellowship program focused on pediatric cancer and blood disorders. DeVos Children’s will recruit one fellow per year for the three-year training program. During the second year and a half of their fellowship, the physicians will work at VARI with our cancer biologists and geneticists, learning cutting-edge technology in cancer gene analysis and aiding our efforts toward new discoveries that will help treat childhood cancers. As you saw on p. iii of this Report, Han-Mo Koo passed away on May 3, 2004, after a sixmonth-long battle with cancer. He joined my laboratory at the National Cancer Institute in Frederick, Maryland, in 1993 as a postdoctoral fellow and came to Grand Rapids with me in 1999. He established the Laboratory of Cancer Pharmacogenetics, and his laboratory was making real progress in showing and understanding the sensitivity of melanoma tumors to inhibitors of the MEK/MAPK pathway. Cancer affects every one of us, and for those of us at VARI, losing beloved friends and colleagues to the disease, like Han-Mo Koo and Dwight Reed, Michelle Reed’s husband, is just terrible. Han-mo spent his life trying to understand and cure cancer, and this has added even more incentive to our search for a cure. We have renamed our seminar series the Han-Mo Koo Memorial Seminar Series. In April 2003, VARI was invited to become a member of the Grand Rapids Clinical Oncology Program (GRCOP). GRCOP is one of the oldest of the 53 NCI community clinical oncology programs (CCOP) in the United States, and we have the unique distinction of being the first basic research institution to affiliate with a CCOP. We anticipate a growing collaboration with them, and we will try to become more involved with the clinical trials network, in addition to the ongoing pancreatic cancer Phase II clinical trial. That pancreatic clinical trial was initiated with GRCOP in 2002, with VARI’s Han-Mo Koo serving as the project’s Research Investigator. The trial has enrolled 21 patients to date and continues; I will substitute for Han-Mo as Research Investigator. 5

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