George F. Vande Woude, PhD

2009-2010 BCRF Project:
Co-Investigator: Ilan Tsarfaty, PhD, Tel Aviv University, Israel

Genome scale analysis of cancer helps researchers to expand their research focus from a few genes to a more complete view of the entire cancerous genetic network. The expression levels or DNA copy number of virtually all genes in a cell can be quantified simultaneously. This more complete analysis of human cancer cells will likely hold the key to solving the difficulties associated with the fact that breast cancer cells comprise complex, robust and evolving systems. Drs. Vande Woude and Tsarfaty are focusing on several aspects of genome scale analysis of human breast cancer.

First, they are developing bioinformatics methods that increase the accuracy of high throughput measurements. Second, from the data sets of increased accuracy they aim to extract quantitative measures of key biological processes in cancer. They are particularly interested in the various subtypes of genomic instability, their relative level in a given breast tumor and whether this could guide more effective therapeutic decisions. Third, the researchers are combining genome scale molecular profiling of chemotherapy-resistant breast cancer cell lines with bioinformatics analysis in order to determine whether clinical response to chemotherapy in breast cancer can be predicted by gene expression signatures derived from cell lines. The most immediate outcome of this research is to develop tools that would predict which breast cancer patient will respond to a given chemotherapeutic agent.

Met is a receptor tyrosine kinase that is aberrantly expressed in more than 30% of breast cancers. High Met expression correlates with poor prognosis independent of Her2/Neu. The goal of the studies led by Drs. Vande Woude and Tsarfaty is to understand the role of Met in breast cancer progression and to develop novel Met-targeted therapeutics and diagnostics. In the past year, they 1) measured the dynamic affects of Met activation on membrane blebbing and cell motility; 2) evaluated the therapeutic effects of Met-targeted therapy with multimodality molecular imaging; 3) investigated Met activation on cancer cell metabolism; 4) validated the prognostic value of a Met signature in breast cancer patients; and 5) examined the differences between Met and ErbB2 signaling in breast cancer progression. The knowledge gained from these studies will contribute to the design and preclinical assessment of Met-targeted therapies as well as early detection modalities for breast cancer.

Mid-Year Progress Report:
Drs. Vande Woude and Tsarfaty have generated novel cellular and laboratory models and imaging modalities for examining the role of Met in breast cancer progression and metastasis. In addition, they are utilizing these models to develop noveldiagnostics and Met-targeted therapeutics. The knowledge gained from these studies will contribute to the design and preclinical assessment of Met-targeted therapies, as well as early detection modalities for breast cancer. In the current grant period, they: 1) examined cellular trafficking of the Met receptor; 2) evaluated Met signaling with multi-modality molecular imaging; 3) investigated Met activation on cancer cell metabolism; 4) validated the prognostic value of a Met signature in breast cancer patients; and 5) examined the differences between Met and ErbB2 signaling in breast cancer progression.

Bio:
Dr. George F. Vande Woude received his M.S. (1962) and Ph.D (1964) from Rutgers University. From 1964-1972, he served first as a postdoctoral research associate, then as a research virologist for the US Department of Agriculture at Plum Island Animal Disease Center. In 1972, he joined the National Cancer Institute as Head of the Human Tumor Studies and Virus Tumor Biochemistry Sections. In 1980, he was appointed Chief of the Laboratory of Molecular Oncology and, in 1983, he was selected to be Director of the Advanced Bioscience Laboratories-Basic Research Program at the National Cancer Institute, Frederick, MD, a position he held until 1998. From 1995-1998, Dr. Vande Woude was Special Advisor to the Director of the National Cancer Institute and served to reorganize the intramural basic science at NCI. In 1999, he was selected to be the first Director of the newly created Van Andel Research Institute in Grand Rapids, Michigan, a position he held until February 2009. He is currently a Distinguished Scientific Fellow.

Dr. Vande Woude was first to use recombinant DNA technology to isolate integrated forms of acute transforming retroviruses and compare their oncogenes to cellular protooncogenes. He was first to determine the structure and sequence of proviral long terminal repeats (LTR), to demonstrate their enhancer function of the LTR promoter, and to show the utility of LTR expression vectors in eukaryotic cells. His laboratory was first to demonstrate that a normal cellular protooncogene could be activated as an oncogene. These findings provided a foundation for the search for active oncogenes in tumors. His studies of the mos oncogene have continued for almost two decades and led to the discovery that the normal mos product regulates vertebrate meiotic maturation and is responsible for the production of an unfertilized egg. The MPF results provided the first direct connection between oncogene function and the cyclin dependent kinases that regulate cell cycle.

Still another important contribution was Dr. Vande Woude's discovery of the human met oncogene, a member of the tyrosine kinase growth factor receptor family that is ubiquitously expressed in mammalian tissues. The Vande Woude lab, together with the laboratory of Dr. Stuart Aaronson, discovered that the Met ligand is a hepatocyte growth factor (HGF). This connection significantly expanded the importance of this ligand-receptor pair in the mitogenic, motogenic, and morphogenic behavior of epithelial cells. His laboratory was first to show that inappropriate Met expression renders cells tumorigenic and occurs in human tumors. His laboratory demonstrated that cells inappropriately expressing HGF/Met autocrine signaling display potent metastatic activity in vivo. This tyrosine kinase growth factor receptor pathway displays all of the phenotypes essential for malignant growth.

Dr. Vande Woude is the recipient of the National Institutes of Health Merit Award, the Robert J. and Claire Pasarow Foundation Award for Cancer Research, and a Lifetime Achievement Award in Technology Transfer from the National Aeronautics and Space Administration. In 1993, he was elected to the National Academy of Sciences and serves as Chair of the Section for Medical Genetics, Hematology & Oncology (2004-present). He served on the Award Assembly of the General Motors Cancer Research Foundation (1990-1994) and serves on the scientific advisory boards of Jefferson Medical College, Thomas Jefferson University (1995- ); Karmanos Cancer Institute & Prentis Comprehensive Cancer Center at Wayne State University (2001- ); US Military Cancer Institute (2001- ); Scientific Advisory Panel, North Shore-Long Island Jewish Research Institute (2002- ). Dr. Vande Woude is a member of the National Dialogue for Cancer (now C-Change) (2001-), served as a member of the Board of Directors for the American Association of Cancer Research (2001-2004), and served on the National Cancer Legislation Advisory Committee (2000-2001). From 2002-2004, Dr. Vande Woude was awarded the Alice Hogge and Arthur A. Baer Professorship and served as Visiting Professor, Department of Radiation and Cellular Oncology, University of Chicago.

Dr. Vande Woude is a member of the American Chemical Society, the American Association for the Advancement of Science, the American Academy of Microbiology, and the American Association for Cancer Research. He is the founder and President of the Foundation for Advanced Cancer Studies (1985- ), which sponsors annual meetings on Oncogenes and Cancer Genetics and Tumor Suppressor Genes that are designed to accommodate and encourage participation by young cancer research investigators.

Dr. Vande Woude is the author of over 240 scientific research articles and over 60 articles in books or monographs. He has served as Editor of Journal of Virology and as an Editorial Board Member of Cell, Cancer Research, and Journal of Virology and is currently an Editorial Board Member of Oncogene, Molecular Imaging, Cell Cycle and Molecular Cancer Research. Dr. Vande Woude was Founding Editor of Cell Growth and Differentiation and, since 1989, has been Co-editor (with George Klein) of Advances in Cancer Research.