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2015 Scientific Report

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Van Andel Research

Van Andel Research Institute | Scientific Report 2015 Brian B. Haab, Ph.D. Laboratory of Cancer Immunodiagnostics Dr. Haab obtained his Ph.D. in chemistry from the University of California at Berkeley in 1998. He then served as a postdoctoral fellow in the laboratory of Patrick Brown in the Department of Biochemistry at Stanford University. Dr. Haab joined VARI as a Special Program Investigator in May 2000, became a Scientific Investigator in 2004, was promoted to Senior Scientific Investigator in 2007, and is now a VARI Professor. He is also an Adjunct Professor in the Department of Biochemistry and Molecular Biology and in the Genetics Program at MSU. From left: Murphy, Partyka, Weaver, Hsueh, Singh, Tang, Ensink, Yadav, Haab Staff Katie Partyka, B.S. Sudhir Singh, Ph.D. Huiyuan Tang, Ph.D. Laura Weaver, A.A.S. Jessica Yadav, M.S. Students Alexander Clegg Elliot Ensink Peter Hsueh, B.S. Anne Murphy, B.S. Alexandria Rogers, B.A. Arkadeep Sinha, B.S. Visiting Scientists Birendra KC, M.D. David VonEhr, B.S., M.Ed. 12

Haab Research Interests The Haab laboratory is working to develop molecular tests that will contribute to improved outcomes for cancer patients. Many cancer patients receive late or inappropriate treatment due to lack of accurate information about their disease. Molecular tests promise to improve that situation. We are developing experimental and bioinformatics methods to identify the carbohydrates and proteins produced only in cancer tissues and are working to define the particular molecular species that are most valuable in clinical tests. We work closely with our clinical partners on pancreatic cancer, addressing problems involving early detection, diagnosis, and treatment decisions. Early diagnosis of pancreatic cancer A blood test that distinguishes early-stage pancreatic cancer from other, benign diseases of the pancreas could have a significant impact on patient care. It could allow patients with early-stage disease to get the appropriate treatment as rapidly as possible; it could be portable to locations distant from major hospitals, thus benefitting a broader population; it could be applied to high-risk individuals as part of a surveillance program to guide the use of more expensive and invasive methods; and it could spare some patients from unnecessary procedures or surgery. We have made good strides toward developing such a test. Carbohydrates, or glycans, cover the surfaces of epithelial cells and decorate nearly all secreted proteins. It has long been recognized that cancer cells rework the glycosylation of their proteins and that the detection of the altered glycans could form the basis of accurate biomarkers. In fact, the current best biomarker for pancreatic cancer is a glycan, a tetrasaccharide known as the sialyl Lewis A (sLeA) antigen. Although the blood level of sLeA is strongly associated with pancreatic cancer—it is elevated in 70–80% of pancreatic cancer patients—it is not satisfactory for diagnosing cancer because the risk of both false negative and false positive diagnoses is too high. The main question we have been asking is, do the cancers that are low in sLeA make other glycans that could be useful biomarkers? If we could find such glycans, they could be used in combination with sLeA to create an effective clinical test. Our recent work provides evidence that this goal is achievable. Some evidence comes from mass spectrometry analyses of pancreatic tissue and gene expression analyses of cell lines, but the best evidence comes from experiments using the antibodylectin sandwich array. With this array, we can efficiently examine all combinations of capture and detection antibodies—each antibody targeting a different glycan—to obtain precise measurements of many glycans in a sample. A study of samples from pancreatic cancer patients and control subjects revealed that the sLeA-low cancers increased their production of several glycans related to sLeA, including a structural isomer of sLeA. We acquired antibodies against those glycans and used them to optimize the detection of the sLeA-low cancers. Furthermore, in collaboration with the Melcher and Xu labs, we produced glycan-binding proteins that provided improved glycan detection in sLeA-low pancreatic cancers. We are consolidating these results into a single, validated test for the detection of early-stage pancreatic cancer. In collaboration with Spectrum Health and others, we are analyzing samples from patients being evaluated for pancreatic issues, and we are performing detailed comparisons between our marker and conventional methods at each stage of patient care. Successful validation of this blood test could be the first step toward achieving a breakthrough in detecting early-stage pancreatic cancer. 13

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