2 years ago

2013 Scientific Report

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  • Report
  • Institute
  • Clinical
  • Molecular
  • Scientific
  • Tumor
  • Laboratory
  • Signaling

George F. Vande Woude,

George F. Vande Woude, Ph.D. Laboratory of Molecular Oncology Dr. Vande Woude received his M.S. and Ph.D. degrees from Rutgers University. In 1972, he joined the National Cancer Institute as head of the Human Tumor Studies and Virus Tumor Biochemistry sections. In 1983, he became director of the Advanced Bioscience Laboratories–Basic Research Program at the Frederick Cancer Research and Development Center, a position he held until 1998. From 1995, Dr. Vande Woude first served as special advisor to the director, and then as director, of the Division of Basic Sciences at NCI. In 1999, he was recruited as the founding Director of VARI. In 2009, Dr. Vande Woude stepped down as Director while retaining his leadership of the Laboratory of Molecular Oncology as a Distinguished Scientific Fellow and Professor. Dr. Vande Woude is a member of the National Academy of Sciences (1993) and a Fellow of the American Academy of Arts and Sciences (2006). From left: Xie, Graveel, Su, Gao, Kang, Essenburg, Vande Woude, Linklater, Yerrum, Staal, Johnson, Zhang, Kaufman Staff Student Adjunct Faculty Curt Essenburg, B.S. Chongfeng Gao, Ph.D. Carrie Graveel, Ph.D. Jennifer Johnson, M.S. Liang Kang, B.S. Dafna Kaufman, M.S. Eric Linklater, B.S. Ben Staal, M.S. Yanli Su, A.M.A.T. Qian Xie, M.D., Ph.D. Smitha Yerrum, M.S. Yu-Wen Zhang, M.D., Ph.D Caroline Muhoro Brian Cao, M.D. 57

Van Andel Research Institute | Scientific Report Research Interests Targeting the MET pathway in glioblastoma Glioblastoma multiforme (GBM) is one of the most devastating cancers. Its hallmark is the invasiveness of the tumor cells infiltrating into normal brain parenchyma, making it virtually impossible to remove the tumor completely by surgery and inevitably leading to recurrent disease. Progress in understanding GBM pathobiology and in developing novel antitumor therapies could be greatly accelerated with animal model systems that display characteristics similar to human GBM and that enable noninvasive tumor imaging in real time. We have established GBM patient-derived xenograft models that preserve tumor genotypes and phenotypes during in vivo passage, and we have isolated stem cell–like cancer populations for preclinical testing of drugs to block tumor growth and invasion. High-throughput, real-time, non-invasive imaging using bioluminescence (BLI) technology can detect orthotopic brain tumor growth before and after treatment. These studies have led to the conclusion that GBM with HGF-autocrine activation acts as if it were MET addicted and displays very high sensitivity to MET inhibitors. A combination of MET inhibitor and the EGFR inhibitor erlotinib showed better anti-tumor efficacy than either drug alone. We are planning further in vivo drug combination studies to try to develop drug strategies that will be more effective in treating MET expression in MET paracrine tumor systems. The role of MET in aggressive breast cancers Understanding the signaling pathways that drive aggressive breast cancers is crucial to the development of effective therapeutics. High expression of the oncogene MET is associated with decreased survival in breast cancer, yet the role it plays in the various breast cancer subtypes is unclear. We are investigating the role of MET in breast cancer progression and metastasis. Using a mouse model and analyses of human tissues, we have found that high MET expression correlates with estrogen receptor-negative/ERBB2-negative tumors and with basal breast cancers. We believe that MET is a key in the development of aggressive breast cancer subtypes and may be a significant therapeutic target. Currently, we are investigating how MET signaling interacts with the ERBB family of receptors in the progression and therapeutic resistance of ERBB2-positive and triple-negative breast cancers. MET as a therapeutic target in human cancers Aberrant activation of the HGF-MET signaling pathway is found in many human cancers, and it promotes cell proliferation, invasion and metastasis. Targeting this pathway is a promising approach to cancer intervention. We are using our unique human-HGF transgenic SCID mice to explore how effective such targeting may be in treating human cancers such as non-small cell lung cancer both in vitro and in vivo. Various MET drugs have been developed, and we are interested in identifying parallel pathways that cross-talk with MET or that are crucial in driving cancer cell resistance to MET drugs. We are also studying the benefits of combination treatments using MET inhibitors together with agents such as EGFR inhibitors. The role of Mig-6 in cancer and joint disease Mig6 is a tumor suppressor gene that functions as a negative feedback regulator in receptor tyrosine kinase signaling, either by direct binding to EGFR/ERBB family receptors or by interactions with signaling molecules downstream of the RTKs. Mig-6 plays an important role in stress responses and tissue homeostasis, and its disruption in mice results in the development of neoplasia and degenerative joint disease. We have shown that Mig6 can be epigenetically silenced and differentially regulated in lung cancer and melanoma cells. Currently, we are investigating the roles and mechanisms of Mig-6 in cancer development and in the maintenance of joint homeostasis. 58

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