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2016 Scientific Report

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Subsequently, our work

Subsequently, our work has focused on characterizing the mechanism of EWS-FLI1 suppression with the goals of understanding the failure in the phase II study, identifying second-generation trabectedin analogs, and developing new mechanism-based combination therapies. We have developed a novel combination therapy of trabectedin plus irinotecan that is synergistic. We have shown that this combination markedly improves the suppression of EWS-FLI1 and substantially increases the DNA damage in Ewing sarcoma cells. We translated this therapy into the clinic in Europe and found it was active in a patient in Italy and in a series of patients in Germany (manuscript in preparation). Since the drug is now approved in the United States, we are writing a phase II protocol for this combination therapy for the Children’s Oncology Group, which will open nationwide for patients with relapsed Ewing sarcoma. Over the past year, we have characterized the mechanism of EWS-FLI1 suppression by trabectedin, and we have shown that mechanism is not effective at the serum concentrations achieved in the failed phase II study, explaining the lack of activity. More importantly, we have identified a second-generation compound with an improved pharmacokinetic profile that will make successful EWS-FLI1 suppression more likely, and we are working to translate this compound to the clinic. We have also extensively studied mithramycin, which reverses EWS-FLI1 activity and blocks the expression of key 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. Over the past year, our work has identified two compounds with an improved clinical profile, one that is more potent and another that is less toxic than the parent compound. Both compounds reverse EWS-FLI1 activity and are extremely active in xenograft models of Ewing sarcoma. Work continues to understand the mechanism of EWS-FLI1 suppression for this class of compounds. We are also taking a broader look at transcription as a Ewing sarcoma drug target, using an siRNA screening platform. We have identified a therapeutic vulnerability based on alternative mRNA splicing, and we are developing companion biomarkers that will accompany our trials and aid in the clinical translation of our EWS-FLI1-directed therapies. We have also identified a commonly employed positron emission tomography (PET) radiotracer that reflects EWS-FLI1 activity in Ewing sarcoma cells, which will allow more precise dosing of our therapies and the direct correlation of EWS-FLI1 activity to PET activity. Finally, we are beginning to expand our studies to other pediatric tumors characterized by oncogenic fusion transcription factors. RECENT PUBLICATIONS Caropreso, Vittorio, Emad Darvishi, Thomas J. Turbyville, Ranjala Ratnayake, Patrick J. Grohar, James B. MacMahon, and Girma Woldenmichael. In press. Englerin A inhibits EWS-FLI1 DNA binding in Ewing’s sarcoma cells. Journal of Biological Chemistry. Osgood, Christy L., Nichole Maloney, Christopher G. Kidd, Susan Kitchen-Goosen, Laura Segars, Meti Gebregiorgis, Girma M. Woldemichael, Min He, Savita Sankar, et al. In press. Identification of mithramycin analogs with improved targeting of the EWS- FLI1 transcription factor. Clinical Cancer Research. Kovar, Heinrich, James Amatruda, Erika Brunet, Stefan Burdach, Florencia Cidre-Aranaz, Enrique de Alava, Uta Dirksen, Wietske van der Ent, Patrick Grohar, et al. 2016. The second European interdisciplinary Ewing sarcoma research summit — a joint effort to deconstructing the multiple layers of a complex disease. Oncotarget 7(8): 8613–8624. 8 Van Andel Research Institute | Scientific Report

BRIAN B. HAAB, PH.D. Dr. Haab obtained his Ph.D. in chemistry from the University of California at Berkeley in 1998. He joined VARI as a Special Program Investigator in 2000, became a Scientific Investigator in 2004, and is now a Professor. STAFF STEPHANIE GRANT, M.P.A. KATIE PARTYKA, B.S. BRYAN REATINI, B.S. SUDHIR SINGH, PH.D. JESSICA SINHA, M.S. HUIYUAN TANG, PH.D. RESEARCH INTERESTS The promise of molecular biomarkers: improving patient outcomes through better detection and subtyping. Tests to detect and diagnose pancreatic cancer STUDENTS DANIEL BARNETT, B.A., B.S. LELAND DUNWOODIE ELLIOT ENSINK PETER HSUEH, B.S. JOEY KRETOWICZ GARIMA VORHA, B.SC., M.B.A. The successful treatment of pancreatic cancer critically depends on achieving an accurate and early diagnosis, but this can be frustratingly difficult. Conventional methods of evaluating patients—assessing scans, visual inspection of cells from a biopsy, and weighing behavioral, health, and demographic data—do not have the detail necessary to distinguish between benign and malignant disease or between cancers with vastly different behaviors. Sometimes a physician can see a mass or other unusual feature in the pancreas but is unsure what it is. Is it benign or cancerous? And if it is cancer, what is the best course of treatment? Our research builds on the concept that molecular-level information will provide details about a condition that are not observable by conventional methods. Molecular biomarkers could provide such information and enable physicians to make accurate diagnoses and develop optimal treatment plans. We are making progress toward this goal for pancreatic cancer. For example, in recent publications in Molecular and Cellular Proteomics and the Journal of Proteome Research, we disclosed carbohydrate-based biomarkers in the blood serum that improve upon the widely used blood test called CA19-9. By using a panel of three or more independent biomarkers, we detected a greater percentage of cancers than we could with any individual biomarker. We are seeking to substantiate those findings and to evaluate their clinical value using serum samples from several clinical sites. CENTER FOR CANCER AND CELL BIOLOGY 9

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