11 months ago

2016 Scientific Report

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ARTHUR S. ALBERTS, PH.D. Dr. Alberts earned his degrees in biochemistry and cell biology (B.A., 1987) and in physiology and pharmacology (Ph.D., 1993) from the University of California, San Diego. He joined VARI in January 2000, and he was promoted to Professor in 2009. STAFF SARAH VANOEVEREN, B.S., B.S. STUDENT ANDREW HOWARD, B.A. VISITING SCIENTIST JULIE TURNER, PH.D. RESEARCH INTERESTS Our lab seeks to gain a full understanding of how cells spatially and temporally organize the biochemical circuits that govern responses to injury, infection, and age. Our goal is to use this information to guide the development of pharmacological agents that block the acquisition of cancer traits. In 2015, we focused our translational research on targeted therapies that reinforce and/or repair blood cell structure and function and otherwise impair the ability of cancer cells to metastasize. RECENT PUBLICATIONS Vargas, Pablo, Paolo Maiuri, Marine Bretou, Pablo J. Sáez, Paolo Pierobon, Mathieu Maurin, Mélanie Chabaud, Danielle Lanakar, Dorian Obino, et al. 2016. Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells. Nature Cell Biology 18(1): 43–53. Arden, Jessica D., Kari I. Lavik, Kaitlin A. Rubinic, Nicolas Chiaia, Sadik A. Khuder, Marthe J. Howard, Andrea L. Nestor-Kalinoski, Arthur S. Alberts, and Kathryn M. Eisenmann. 2015. Small molecule agonists of mammalian Diaphanous-related (mDia) formins reveal an effective glioblastoma anti-invasion strategy. Molecular Biology of the Cell 26(21): 3704–3718. Ercan-Sencicek, A. Gulhan, Samira Jambi, Daniel Franjic, Sayoko Nishimura, Mingfeng Li, Paul El-Fishawy, Thomas M. Morgan, Stephan J. Sanders, Kaya Bilguvar, Mohnish Suri, et al. 2015. Homozygous loss of DIAPH1 is a novel cause of microcephaly in humans. European Journal of Human Genetics 23(2): 165–172. 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. STAFF MATT EASTON SUSAN GOOSEN, B.S., M.B.A. MATT HARLOW, M.S. DIANA LEWIS, A.S. 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 formed by chromosomal translocations. In many cases, the tumors depend on the continued expression and activity of those transcription factors for cell survival, but few therapies that directly target specific factors have achieved clinical efficacy. Therefore, we are developing new approaches to target those transcription factors. To date, we have focused on targeting the EWS-FLI1 transcription factor in Ewing sarcoma. EWS-FLI1 is an oncogenic transcription factor formed by the t(11;22)(q24;12) chromosomal translocation that leads to the fusion of the EWSR1 and FLI1 genes. The result is a dysregulated transcription factor that alters the expression of over 500 genes and drives tumorigenesis and progression. Several independent studies have shown that silencing of EWS-FLI1 is incompatible with Ewing sarcoma cell survival. By directly targeting EWS-FLI1, we hope to eliminate its activity as the dominant oncogene in this tumor and thus improve patient survival. Trabectedin (ET-743; ecteinascidin 743; Yondelis) is a natural product originally isolated from the sea squirt, Ectenascidia turbinata. We became interested in this compound because early clinical studies suggested that translocation-positive sarcomas were sensitive to it. We subsequently demonstrated that trabectedin blocks EWS-FLI1 activity at the promoter, mRNA, and protein levels of expression. In addition, we demonstrated on a genome-wide scale that it reverses the expression of the gene signature of EWS- FLI1. However, the compound failed in a phase II study on Ewing sarcoma. CENTER FOR CANCER AND CELL BIOLOGY 7

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