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2002 Scientific Report

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Laboratory of Cancer

Laboratory of Cancer Pharmacogenetics Han-Mo Koo, Ph.D. Dr. Koo received his Ph.D. in microbiology and molecular genetics at Rutgers–The State University of New Jersey in 1993. He then served as a Senior Postdoctoral Fellow in the laboratory of George Vande Woude in the Molecular Oncology Section of the Advanced BioScience Laboratories–Basic Research Program at the National Cancer Institute–Frederick Cancer Research and Development Center, Maryland. In June 1999, Dr. Koo joined VARI as a Scientific Investigator. Laboratory Members Staff Kate Eisenmann, Ph.D. Matt VanBrocklin, M.S. Nancy Staffend, B.S. Students Susan Kitchen Tracey Millard Research Projects Advances in our understanding of the molecular pathophysiology of human cancers open promising opportunities for the prevention of and intervention in cancer. Our laboratory is interested in studying mechanisms of drug actions, identifying novel therapeutic targets, and developing novel anticancer agents by means of molecular-targeting approaches. Mitogen-activated protein kinase (MAPK) signaling pathways are highly conserved among all eukaryotes and are integral for the transduction of a variety of extracellular signals. Furthermore, constitutive activation of MAPK signaling (e.g., the Raf-MEK1/2-ERK1/2 pathway) contributes to many aspects of human cancers; hence, the pathway has been identified as a potential therapeutic target for cancer intervention. Typically, cancer cells exhibit a cytostatic (growth arrest) response to the disruption of MAPK signaling. However, we have recently demonstrated that interfering with the MAPK signaling pathway evokes a cytotoxic response (apoptosis) in human melanoma cells but not in normal melanocytes: either anthrax lethal toxin (which proteolytically cleaves MAPK kinases [MEKs]) or small-molecule MEK inhibitors (such as PD90859 and U0126) triggers an apoptotic response in human melanoma cells. Normal melanocytes treated with the same inhibitors, on the other hand, simply arrest in the G1 phase of the cell cycle. More importantly, in vivo treatment with anthrax lethal toxin of human melanoma xenograft tumors in athymic nude mice renders either significant or complete tumor regression without apparent side effects. These results indicate that the MAPK signaling pathway represents a tumor-specific survival signaling in melanoma and that inhibition of this pathway may be a useful and potentially selective strategy for treating this cancer. Our current research focuses on molecular characterization of the MAPK pathway–associated survival signaling in melanoma cells. In particular, we are investigating the phosphorylation and inactivation of the pro-apoptotic protein Bad mediated by the 90 kDa ribosomal S6 kinase. The molecular mechanism by which the inhibition of MAPK signaling specifically triggers apoptosis in human melanoma cells should reveal additional molecular targets useful for prevention of and intervention in melanoma, as well as in other MAPK-associated cancers such as pancreatic, lung, colon, and breast carcinomas, as well as gliomas. Additionally, further validation studies are ongoing to clinically develop the MAPK signaling pathway as a therapeutic target for melanoma treatment. Activating mutations in RAS oncogenes are the most frequent gain-of-function mutations detected in human cancers. Besides their welldocumented role in cellular transformation and tumorigenesis, we have previously shown that the RAS oncogenes play an important role in sensitizing tumor cells to deoxycytidine analogues such as 1-β-D-arabinofuranosylcytosine (Ara-C) and gemcitabine, as well as to topoisomerase (topo) II inhibitors, more prominently to etoposide. These results are supported by clinical findings that patients who have RAS onco- 31

gene–positive acute myeloid leukemia show an increased remission rate, longer remission duration, and improved overall survival in response to a combination therapy of Ara-C plus topo II inhibitor. To translate our results into a clinical trial, we have established a collaboration with the Grand Rapids Clinical Oncology Program and the Spectrum Health Cancer Program. This summer, through this collaboration, we have initiated a Phase II trial to evaluate the gemcitabine + etoposide combination treatment for patients with locally advanced or metastatic pancreatic carcinomas, which display RAS oncogene activation in over 95% of the cases. External Collaborators Thomas M. Aaberg, Jr., Associated Retinal Consultants, Grand Rapids, Michigan Alan Campbell, Spectrum Health Cancer Program, Grand Rapids, Michigan Marianne K. Lang, Timothy J. O’Rourke, and Connie Szczepanek, Grand Rapids Clinical Oncology Program, Michigan Won Kyu Lee, Kent Pathology Laboratory, Ltd., Grand Rapids, Michigan Judith S. Sebolt-Leopold, Pfizer Global Research & Development, Ann Arbor, Michigan Lilly Research Laboratories, a division of Eli Lilly and Company, Indianapolis, Indiana Publications Koo, Han-Mo, Nicholas S. Duesbery, and George F. Vande Woude. 2002. Anthrax toxins, mitogenactivated protein kinase pathway, and melanoma treatment. Directions in Science 1: 123–126. Koo, Han-Mo, Matt VanBrocklin, MaryJane McWilliams, Stephan H. Leppla, Nicholas S. Duesbery, and George F. Vande Woude. 2002. Apoptosis and melanogenesis in human melanoma cells induced by anthrax lethal factor inactivation of mitogen-activated protein kinase kinase. Proceedings of the National Academy of Sciences U.S.A. 99(5): 3052–3057. From left to right: Kitchen, VanBrocklin, Millard, Staffend, Eisenmann, Koo 32

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