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2016 Scientific Report

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Other research is aimed

Other research is aimed at further improving the biomarker tests. The results so far suggest that each individual biomarker arises from a distinct subpopulation of cancer patients and from a characteristic cell type. This finding is important because the biomarkers may reveal differences between subgroups of tumors—a possibility we are exploring in the research described below. For the purpose of improving our blood tests, determining the characteristics of the cells that produce each biomarker, as well as of the cells that do not produce any of our biomarkers, will help to optimize a blood test to accurately identify cancers across the entire spectrum of patients. The ultimate goal is to get the new tests established in clinical laboratories in order to benefit patients. To that end, we are working with industry partners to transfer our biomarker assays to the clinical laboratory setting and to begin analyzing patient samples received consecutively from clinical sites. If we have good results, we hope to initiate clinical trials for the diagnosis of pancreatic cancer and, eventually, for evaluations of surveillance among people at elevated risk for pancreatic cancer. Better treatment through subtyping Pancreatic cancer characteristics, such as the cell types within the tumor, the amount of metastasis, the responses to treatments, and overall outcomes, vary greatly among patients. So far, identifying the underlying causes of such differences and predicting the behavior of individual tumors have not been possible. If we could determine what drives the differences between the tumors or identify molecules that help predict the behavior of each tumor, we could establish better treatment plans for each patient or determine the drugs that work best against each subtype. Our research is revealing major groupings of tumors based on the carbohydrates on the surface of, and in the secretions from, cancer cells. The carbohydrates are related to the CA19-9 antigen and have distinct biological functions. In current research we want to determine the molecular nature of the subgroups of cells and whether the subgroups have different levels of aggressiveness or different responses to particular drugs. We are using new approaches for measuring carbohydrates and proteins in tumor tissue, and we are employing powerful new software—introduced in our recent publication in Analytical Chemistry—to examine the cell types that produce each carbohydrate-based biomarker. We are using that information to evaluate whether certain types of cells predict clinical behavior. As advances and new options in treatments become available, this type of research is increasingly important for guiding clinical decisions. We are working closely with our physician collaborators to evaluate on a case-by-case basis the value of the molecular information and to guide our research toward improving the tests. Ultimately, physicians could use the molecular tests on material from biopsies, surgical resections, or blood samples. RECENT PUBLICATIONS Ensink, Elliot, Jessica Sinha, Arkadeep Sinha, Huiyuan Tang, Heather M. Calderone, Galen Hostetter, Jordan Winter, David Cherba, Randall E. Brand, et al. 2015. Segment and fit thresholding: a new method for image analysis applied to microarray and immunofluorescence data. Analytical Chemistry 87(19): 9715–9721. Singh, Sudhir, Kuntal Pal, Jessica Yadav, Huiyuan Tang, Katie Partyka, Doron Kletter, Peter Hsueh, Elliot Ensink, Birendra KC, et al. 2015. Upregulation of glycans containing 3' fucose in a subset of pancreatic cancers uncovered using fusion-tagged lectins. Journal of Proteome Research 14(6): 2594–2605. Tang, Huiyuan, Sudhir Singh, Katie Partyka, Doron Kletter, Peter Hsueh, Jessica Yadav, Elliot Ensink, Marshall Bern, Galen Hostetter, et al. 2015. Glycan motif profiling reveals plasma sialyl-Lewis X elevations in pancreatic cancers that are negative for CA19-9. Molecular & Cellular Proteomics 14(5): 1323–1333. 10 Van Andel Research Institute | Scientific Report

YUANZHENG (AJIAN) HE, PH.D. Dr. He earned his Ph.D. from the Chinese Academy of Sciences’ Shanghai Institute of Biochemistry in 2000. In 2008, he was recruited to Van Andel Research Institute, where he is currently a Research Assistant Professor. RESEARCH INTERESTS Ligand binding is the key event that triggers intracellular signal transduction cascades, and it is also a major focus of drug discovery. My research involves the structural basis of ligand/receptor interactions and related drug discovery, focusing on steroid hormone receptors, specifically, the glucocorticoid receptor and the G protein–coupled receptors (GPCRs). My overall goal is to explore structural insights into receptor signaling and use them to design precision drugs that specifically deliver the desired treatment effect, but not unwanted side effects, to patients. Over the past year, we have made the following progress. • We have developed “dissociated glucocorticoid” molecules based on our finding that the dissociation of transrepression from transactivation can be achieved by interfering with the dimerization interface of the glucocorticoid receptor. • We have developed an exceptionally potent glucocorticoid for asthma treatment based on our uncovering of the structural key to glucocorticoid potency. Our primary compound outperforms the current leading drug in a mouse asthma model and promises a better side-effects profile. • We have determined the structure of arrestin-bound rhodopsin, which provides a basis for understanding GPCR-mediated arrestin-biased signaling. RECENT PUBLICATIONS Kang, Yanyong, Xiang Gao, X. Edward Zhou, Yuanzheng He, Karsten Melcher, and H. Eric Xu. 2016. A structural snapshot of the rhodopsin–arrestin complex. FEBS Journal 283(5): 816–821. He, Yuanzheng, Jingjing Shi, Wei Yi, Xin Ren, Xiang Gao, Jianshuang Li, Nanyan Wu, Kevin Weaver, Qian Xie, et al. 2015. Discovery of a highly potent glucocorticoid for asthma treatment. Cell Discovery 1: 15035. Zhi, Xiaoyong, X. Edward Zhou, Yuanzheng He, Kelvin Searose-Xu, Chun-Li Zhang, Chih-Cheng Tasi, Karsten Melcher, and H. Eric Xu. 2015. Structural basis for corepressor assembly by the orphan nuclear receptor TLX. Genes and Development 29(4): 440–450. CENTER FOR CANCER AND CELL BIOLOGY 11

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