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2009 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report Research Interests Many malignant sarcomas such as fibrosarcomas are refractory to available treatments. However, sarcomas possess unique vascular properties which indicate they may be more responsive to therapeutic agents that target endothelial function. Mitogenactivated protein kinase kinases (MKKs) play an essential role in the growth of carcinomas, and we hypothesize that signaling through multiple MKK pathways is also essential for sarcomas. One objective of our research is to define the role of MKK signaling in the growth and vascularization of human sarcomas and to determine whether MKK inhibitors can form the basis of a novel and innovative approach to the treatment of human sarcoma. In 2008, we published a study showing that inhibition of MKK signaling by lethal toxin (LeTx) caused a rapid and dramatic decrease in tumor perfusion that was followed by a long-term reduction in tumor vascularization. Follow-up histologic analysis in collaboration with VARI’s James Resau (Laboratory of Analytical, Cellular, and Molecular Microscopy) showed this acute decrease in tumor perfusion was caused by increased leakiness of tumor blood vessels. This was unexpected, because antiangiogenic agents typically lead to a regression of neovascularization over the course of weeks, not hours. Moreover, these agents typically normalize tumor-associated blood vessels, rendering them less leaky. The results of our study show that while MKK activity is required for tumor cell proliferation, it also plays an important role in tumor vascular function. With funding from the Elsa Pardee Foundation, we have continued our investigation of the effects of MKK inhibition on vascular function in sarcomas. In parallel, Jenn Bromberg-White, a postdoctoral fellow, has begun an investigation into the roles MKK pathways play in the formation of vascular networks in the developing mouse eye, while Chih-Shia Lee, a graduate student, is performing a detailed study of the individual contributions of MKK pathways to melanoma survival. In 2008 we also began a new project on hemangiosarcomas, a soft-tissue tumor for which there are currently no effective treatments. Although rare in humans, hemangiosarcomas are relatively common in certain breeds of dogs such as Golden Retrievers, German Shepherds, and Clumber Spaniels. Hemangiosarcomas seem to run in families, indicating that there is an underlying hereditary or genetic component to this disease. To study these tumors, we have established the Canine Hereditary Cancer Consortium (CHCC). With the support of the American Kennel Club Canine Health Foundation (AKC CHF Grant 1114) and the Clumber Spaniel Health Foundation, the CHCC will take advantage of new genetic resources and technologies at Van Andel Research Institute to develop genetic screens, diagnostic tests, and treatments for hereditary canine cancers, as well as to gain insight into the biology of human disease. In our pilot proposal, we have focused on hemangiosarcomas in Clumber Spaniels; later we will include other breeds and additional hereditary cancers. We will analyze collected DNA and RNA samples from Clumber Spaniels for genetic patterns that are associated with this disease. These patterns may form the basis of genetic tests that can tell us whether a particular dog is a carrier of a defective gene that will cause cancer. Also, these studies may provide important clues about hemangiosarcomas in humans. Key laboratories participating in this project include the Laboratory of Cancer Genetics; the Laboratory of Analytical, Cellular, and Molecular Microscopy; the Laboratory of Computational Biology; and the Laboratory of Cancer & Developmental Cell Biology. Dr. Roe Froman, D.V.M., is our consulting veterinarian. 18

VARI | 2009 Recent Publications Alfano, Randall W., Stephen H. Leppla, Shihui Liu, Thomas H. Bugge, Cynthia J. Meininger, Terry C. Lairmore, Arlynn F. Mulne, Samuel H. Davis, Nicholas S. Duesbery, and Arthur E. Frankel. 2009. Matrix metalloproteinase– activated anthrax lethal toxin inhibits endothelial invasion and neovasculature formation during in vitro morphogenesis. Molecular Cancer Research 7(4): 452–461. Bromberg-White, Jennifer L., Elissa Boguslawski, and Nicholas S. Duesbery. 2009. Perturbation of mouse retinal vascular morphogenesis by anthrax lethal toxin. PLoS One 4(9): e6956. Alfano, Randall W., Stephen H. Leppla, Shihui Liu, Thomas H. Bugge, Meenhard Herlyn, Keiran S. Smalley, Jennifer L. Bromberg-White, Nicholas S. Duesbery, and Arthur E. Frankel. 2008. Cytotoxicity of the matrix metalloproteinase– activated anthrax lethal toxin is dependent on gelatinase expression and B-RAF status in human melanoma cells. Molecular Cancer Therapeutics 7(5): 1218–1226. 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, et al. 2008. Mitogen-activated protein kinase kinase signaling promotes growth and vascularization of fibrosarcoma. Molecular Cancer Therapeutics 7(3): 648–658. Kuo, Shu-Ru, Mark C. Willingham, Sarah H. Bour, Elissa A. Andreas, Seong Kyu Park, Carney Jackson, Nicholas S. Duesbery, Stephen H. Leppla, Wei-Jen Tang, and Arthur E. Frankel. 2008. Anthrax toxin–induced shock in rats is associated with pulmonary edema and hemorrhage. Microbial Pathogenesis 44(6): 467–472. From left: Lee, Boguslawski, Holman, Duesbery, Froman, Bromberg-White; foreground: D Too, a Clumber Spaniel 19

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