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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 Nicholas S. Duesbery, Ph.D. Laboratory of Cancer and Developmental Cell Biology Dr. Duesbery received a B.Sc. (Hon.) in biology (1987) from Queen’s University, Canada, and both his M.Sc. (1990) and Ph.D. (1996) degrees in zoology from the University of Toronto under the supervision of Yoshio Masui. Before his appointment at VARI in 1999, he was a postdoctoral fellow in George Vande Woude’s laboratory at the National Cancer Institute, Frederick Cancer Research and Development Center, Maryland. Dr. Duesbery was promoted to Associate Professor in 2006, and he chairs VARI’s Undergraduate Internship Program Committee. From left, seated: Kuk, Naidu; standing: Bromberg-White, Boguslawski, Minard, Andersen, Rocky, Duesbery, Marritt, Kramer Staff Nicholas Andersen, Ph.D. Elissa Boguslawski Jenn Bromberg-White, Ph.D. Michelle Minard Students Holly Kramer Cynthia Kuk, B.S. Eimi Marritt Agni Naidu, B.S., B.A. Adjunct Faculty Christopher Chambers, M.D., Ph.D. Lou Glazer, M.D. Barbara Kitchell, D.V.M., Ph.D., DACVIM 8

Duesbery Research Interests Several years ago we discovered that turning off mitogen-activated protein kinase kinases (MKKs) reduces blood vessel density in tumors and causes them to stop growing or to shrink. Since then we have focused our efforts on defining the role of MKK signaling in blood vessel function in cancer and vascular disease, whose pathogeneses rely upon abnormal blood vessel formation. Our goal is to develop new therapies to control blood vessel growth in disease. Our scientific projects are organized around four diseases of blood vessels, affording a unique opportunity to compare and contrast the relationship between MKK signaling and blood vessel growth during development and disease. Project 1) We discovered that MKK inhibition by anthrax lethal toxin causes tumor hemorrhage, reduces blood flow, and lowers blood vessel density. To explain this, we are testing the scientific hypothesis that anthrax lethal toxin acts like a hemorrhagic toxin, disrupting tumor blood vessel function by breaking elements that hold blood vessels together. Our goal is to develop new ways to prevent tumor blood vessel growth and shrink tumors. Project 2) We have found that MKK inhibition blocks growing blood vessels in the retina but does not affect fully grown blood vessels. We also discovered that the vitreous of patients with proliferative diabetic retinopathy has higher amounts of several small inflammatory proteins. To explain clinical resistance to current therapy, we are testing the scientific hypothesis that one or more of these small inflammatory proteins activates MKK signaling and turns on retinal blood vessel growth. Our goal is to develop new anti-MKK therapies to prevent abnormal blood vessel growth in diseases like proliferative diabetic retinopathy. Project 3) We discovered that turning on MKK drives the growth of a rare tumor type called angiosarcoma. Using mouse models, we showed that treatment of angiosarcoma with drugs causes these tumors to shrink. We are currently testing MKK inhibitors in combination with other anti-cancer drugs, working to develop more effective therapies for treating angiosarcoma and other sarcomas. Project 4) We have found that MKK is essential for the regrowth of blood vessels following injury or artery blockage. We are testing the hypothesis that activation of MKK in the cells that form blood vessels makes those cells divide and grow to expand existing blood vessels as well as to make new ones. Our goal is to better understand this process in order to develop therapies that will speed the recovery of blood vessel function following injury or blocking of the arteries. Recent Publications Andersen, Nicholas J., Brian J. Nickoloff, Karl J. Dykema, Elissa A. Boguslawski, Roman I. Krivochenitser, Roe E. Froman, Michelle J. Dawes, Laurence H. Baker, Dafydd G. Thomas, et al. 2013. Pharmacologic inhibition of MEK signaling prevents growth of canine hemangiosarcoma. Molecular Cancer Therapeutics 12(9): 1701–1714. Bromberg-White, Jennifer L., Louis Glazer, Robert Downer, Kyle Furge, Elissa Boguslawski, and Nicholas Duesbery. 2013. Identification of VEGF-independent cytokines in proliferative diabetic retinopathy vitreous. Investigative Ophthalmology and Visual Science 54(10): 6472–6480. Ding, Ximin Chen, Jin Zhu, Nicholas S. Duesbery, Xunjia Cheng, and Brian Cao. 2013. A human/murine chimeric Fab antibody neutralizes anthrax lethal toxin in vitro. Clinical and Developmental Immunology 2013: 475809. 9

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