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2018 Scientific Report

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Center for Cancer and

Center for Cancer and Cell Biology 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 ChongFeng Gao, Ph.D. Zachary Klamer, B.S. Ying Liu, Ph.D. Katie Partyka, B.S. Ben Staal, M.S. Jeanie Wedberg, A.S. Luke Wisniewski, B.S. STUDENTS RESEARCH INTERESTS Patients facing a possible diagnosis of cancer need answers to such fundamental questions as whether a lesion is cancerous and, if so, which treatment will work best, yet getting the answers can be difficult. The heterogeneity of cancers of a particular organ is a major source of the difficulty. For example, for pancreatic cancer, physicians do not have tests that reliably distinguish cancerous from noncancerous lesions or that group the cancers into specific subtypes. To address this need, we are 1) seeking molecular markers to identify the subtypes of pancreatic cancer cells; 2) determining the behavioral and biological differences between the subtypes; and 3) developing assays to detect the subtypes in a clinical setting. With such assays, we hope to improve the ability to detect and diagnose pancreatic cancers, to enable prediction of the behavior of each cancer, and to guide studies aimed at treating each subtype. We found that a carbohydrate structure, which we named the sTRA antigen, is produced by a subtype of pancreatic cancer cell that is different from typical cancer cells. We also found that another carbohydrate, the well-known CA19-9 antigen, identifies a separate type of pancreatic cancer cell. Individual tumors may have cancer cells producing one, both, or neither of the antigens. Our research is revealing that the sTRA-producing cancer cells are more resistant to death and more aggressive than the CA19-9-producing cells. We are seeking to clarify the nature and mechanisms of the differences between the subtypes and to determine optimal treatments for each. Both antigens are secreted into the blood, so we are investigating the use of blood tests for sTRA and CA19-9 to identify more pancreatic cancers than previously possible and to determine their subtype. We are also using new methods of carbohydrate analysis developed in our lab to find markers for additional subtypes of pancreatic cancer cells. David Ayala-Talavera Daniel Barnett, B.A., B.S. Anna Barry, B.S. Johnathan Hall Peter Hsueh, B.S. Hannah Kalee 8 | VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT

XIAOHONG LI, Ph.D. Dr. Li received her Ph.D. from the Institute of Zoology, Chinese Academy of Sciences, in Beijing in 2001. She joined VARI as an Assistant Professor in September 2012. RESEARCH INTERESTS Our laboratory is committed to understanding tumor dormancy and cancer bone metastasis. Our long-term goals are to develop better therapeutic approaches for bone metastasis and to prolong a dormancy-permissive bone microenvironment so that cancer cells can be killed while they are in that state. STAFF Sourik Ganguly, Ph.D. Alexandra Vander Ark, M.S. Jeanie Wedberg, A.S. Erica Woodford, B.S. Project 1. Influence of the bone microenvironment on drug resistance in prostate cancer bone metastasis. Second-line hormonal therapies such as enzalutamide improve overall patient survival by only a few months in about 50% of patients, and almost all patients develop drug resistance. Thus, we need to determine the mechanisms of drug resistance and to develop new approaches for overcoming it. Based on our studies, the goals of this project are to determine how enzalutamide decreases TGFBR2 in osteoblasts, to investigate how loss of TGFBR2 in osteoblasts promotes the progression of prostate cancer bone metastases, and to target the underlying mechanism as a novel therapeutic approach to overcoming enzalutamide resistance. Project 2. Influence of the bone microenvironment on prostate cancer dormancy. The majority of cancer patients die of metastases that begin years or decades after primary diagnosis and treatment. Up to 70% of prostate cancer patients have disseminated tumor cells in the bone marrow at the time of initial diagnosis, and these cells can remain dormant and reactivate later. Understanding the underlying mechanism will provide novel avenues for early preventive and therapeutic approaches to eradicating metastatic recurrence. We have created a mouse model in which prostate cancer bone metastasis development is delayed by four weeks, which is equivalent to three years in humans. Based on our studies, we are proposing to test the effect of blocking CTHRC1 or of vitamin C treatment on prostate cancer dormancy and bone metastasis. VAN ANDEL RESEARCH INSTITUTE SCIENTIFIC REPORT | 9

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