11 months ago

2018 Scientific Report

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  • Institute
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Center for Cancer and

Center for Cancer and Cell Biology JUAN DU, Ph.D. Dr. Du earned her Ph.D. at the University of Freiburg. She joined the VARI faculty in October 2017 as an Assistant Professor. RESEARCH INTERESTS The lab is focused on understanding the mechanism and pharmacology of excitatory neuronal receptors, which are crucially involved in numerous neurological diseases. A combined approach of single-particle cryo-EM, patch-clamp electrophysiology, and X-ray crystallography is employed to study the atomic structures and biological functions of these ion channel receptors. STAFF Chen Fan, Ph.D. Michelle Martin, A.A. 6 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

PATRICK J. GROHAR, M.D., Ph.D. Dr. Grohar earned his Ph.D. in chemistry and his M.D. from Wayne State University. He joined VARI in 2015 as an Associate Professor, and he has clinical and research responsibilities at Spectrum Health and Michigan State University, respectively. RESEARCH INTERESTS Our laboratory studies pediatric sarcomas, and our goal is to develop novel, molecularly targeted therapies and to translate those therapies into the clinic. Most pediatric sarcomas are characterized by oncogenic transcription factors that are required for cell survival. We are developing new approaches to target those molecules. STAFF Elissa Boguslawski, R.L.A.T. Jenna Gedminas, M.D. Susan Goosen, B.S., M.B.A. Mitchell McBrairty, B.S. Michelle Minard, B.S. Brandon Oswald, B.S. Erik Peterson, B.S., M.S. Katie Sorensen, B.S. STUDENTS Maggie Chasse, M.S. Guillermo Flores, B.S. Trabectedin is a natural product originally isolated from the sea squirt, Ecteinascidia turbinata. Our recent work has focused on characterizing the mechanism of trabectedin’s suppression of the EWS-FLI1 transcription factor in Ewing sarcoma, identifying second-generation trabectedin analogs, and developing new combination therapies. We showed that the drug works by redistributing EWS-FLI1 within the nucleus to the nucleolus. This mechanism provides justification for using a secondgeneration compound, lurbinectedin, which maintains the nuclear redistribution of EWS-FLI1 but accumulates to higher serum concentrations. Over the past year, we have shown convincingly that a targeted combination therapy of trabectedin plus irinotecan provides cooperative suppression of EWS-FLI1. Irinotecan augments and sustains suppression of EWS-FLI1 in vivo, leading to the differentiation of Ewing sarcoma cells into benign tissue. We have also shown that lurbinectedin maintains both this synergy with irinotecan and the mechanism of synergy. We have a number of anecdotal responses to treatment with trabectedin plus irinotecan, and responses to lurbinectedin have been seen in patients in two independent studies. We are working to formally evaluate these combinations in phase II studies in the United States. We have also extensively studied mithramycin, which reverses EWS-FLI1 activity and blocks the expression of key EWS-FLI1 downstream targets. In a phase I/II trial at the National Cancer Institute, we found that mithramycin did not achieve serum levels high enough to block EWS-FLI1 activity. We have now identified secondgeneration compounds with improved properties that show excellent activity in Ewing sarcoma cells. We are extending these findings to other tumor types. We have shown that cells deficient in components of the SWI/SNF chromatin remodeling complex are hypersensitive to mithramycin. Work is in progress to understand the mechanism of this hypersensitivity. We are also exploring the interface of epigenetics and transcription as a drug target. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 7

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