SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M VINATA B. LOKESHWAR, PH.D. Associate Professor of Urology DESCRIPTION OF RESEARCH Dr. Lokeshwar’s research focuses on understanding the mechanism of cancer progression and tumor angiogenesis. Recent advances in cancer research have elucidated that the components of extracellular matrix (ECM) and ECMdegrading enzymes play a crucial role in regulating both the metastatic progression of localized tumors and tumor angiogenesis. Using bladder and prostate cancer model systems, she and her colleagues are trying to understand how ECM affects tumor metastasis and angiogenesis. Work in Dr. Lokeshwar’s laboratory demonstrates that an ECM component, hyaluronic acid (HA, which is a glycosaminoglycan), and its degrading enzyme, hyaluronidase (HAase), are closely associated with the biology of cancers of the bladder and prostate. They observed that elevated urinary HA and HAase levels are diagnostic indicators of bladder cancer and its grade, respectively. This finding has led to the development of a simple, noninvasive, highly sensitive, and specific urine test (HA-HAase test; 90 percent accuracy) for detecting bladder cancer and monitoring its recurrence. Dr. Lokeshwar’s research on prostate cancer showed that immunohistochemical localization of both HA and HAase in prostate cancer tissues is greater than 85 percent accurate in predicting prognosis for prostate cancer patients and is better than CD44v6 and microvessel density. Furthermore, both HAase and the HA-HAase combination are independent predictors of prognosis. Thus, use of these markers in biopsy specimens may help clinicians to make individualized treatment decisions and improve patients’ prognosis. In their efforts to understand the function of tumor-derived HAase, the researchers purified and cloned the first tumor-derived HAase. They have demonstrated that this tumor-derived HAase degrades tumor-associated HA into small angiogenic fragments, which then interact with a HA receptor, RHAMM, on endothelial cells. The HA fragments and RHAMM interaction on the cell surface induces signaling events, resulting in the stimulation of endothelial cell functions such as proliferation through the mitogen-activated protein kinase (MAPK). Endothelial cell proliferation is of key importance in tumor angiogenesis. Their recent work, using an antisense cDNA transfection strategy, demonstrates that tumorderived HAase is necessary for tumor growth and muscle invasion of bladder tumors. This is an important finding since 60 percent of bladder cancer patients with muscle invasive disease die within five years. Currently, Dr. Lokeshwar’s research efforts focus on the following areas. First, researchers are comparing the efficacy of the HA-HAase test with other FDA-approved bladder tumor markers for monitoring bladder cancer recurrence. Second, they are testing the potential of HAase and HA-HAase to predict prognostic potential using prostate biopsy specimens. Thirdly, they are investigating the functions of HAase and HAsynthase enzymes in bladder and prostate cancer growth and progression. SELECTED PUBLICATIONS 2002 Lokeshwar, VB and Soloway, MS. Re: Urine based markers of urological malignancy. Journal of Urology 167:1406-07, 2002. Lokeshwar, VB , Schroeder, GL, Selzer, MG, Hautmann, SH, Posey, JT, Duncan, RC, Watson, R, Rose, L, Markowitz, S, and Soloway, MS. Bladder tumor markers for monitoring recurrence and screening comparison of hyaluronic acid-hyaluronidase and BTA-Stat tests. Cancer 95:61-72, 2002. Ekici, S and Lokeshwar, VB . Mesane tumoru belirleyicileri ve HA-HAase testi. Uroloji Bulteni 13:133-40, 2002. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 47
C L I N I C A L O N C O L O G Y R E S E A R C H P R O G R A M Lokeshwar, VB , Schroeder, GL, Carey, RI, Soloway, MS, and Iida, N. Regulation of hyaluronidase activity by alternative mRNA splicing. Journal of Biological Chemistry 277:33654-63, 2002. 2003 Dandekar, DS, Lokeshwar, VB , Cevallos- Arellano, E, Soloway, MS, and Lokeshwar, BL. An orally active Amazonian plant extract (BIRM) inhibits prostate cancer growth and metastasis. Cancer Chemotherapy and Pharmacology 52:59- 66, 2003. Simon, MA, Lokeshwar, VB , and Soloway, MS. Current bladder cancer tests: unnecessary or beneficial? Critical Reviews in Oncology/Hematology 47:91-107, 2003. Franzmann, EJ, Schroeder, GL, Goodwin, WJ, Weed, DT, Fisher, P, and Lokeshwar, VB . Expression of tumor markers hyaluronic acid and hyaluronidase (HYAL1) in head and neck tumors. International Journal of Cancer 106:438-45, 2003. Posey, JT, Soloway, MS, Ekici, S, Sofer, M, Civantos, F, Duncan, RD, and Lokeshwar, VB. Evaluation of the prognostic potential of hyaluronidase activity by alternative mRNA splicing. Journal of Biological Chemistry 277:33654-63, 2002. HIGHLIGHTS/DISCOVERIES • Developed the HA-HAase urine test, a noninvasive test that is about 90 percent accurate in detecting bladder cancer and monitoring its recurrence. • Established that HA and HAase are greater than 85 percent accurate prognostic indicators for prostate cancer. • Demonstrated the function of tumor-derived HAase in bladder tumor growth and muscle invasion. IZIDORE LOSSOS, M.D. Associate Professor of Medicine DESCRIPTION OF RESEARCH By examining gene expression profiles in diffuse large B-cell lymphomas (DLBCL) and applying a pattern recognition algorithm-termed hierarchical clustering, Dr. Lossos’ laboratory identified at least two molecularly distinct forms of the disease. These were defined by specific gene expression signatures: germinal center (GC) B cell-like DLBCL characterized by expression of genes normally expressed in GC B cells, and having a significantly better overall survival than the activated B cell (ABC)-like DLBCL characterized by expression of genes normally induced during in vitro activation of B cells. Discovery of new DLBCL tumor categories with distinct outcomes by gene expression data suggested that lymphomagenesis mechanisms involved in the establishment or progression of these tumors may be distinct. Indeed, researchers in this laboratory and others have demonstrated that: 1) the t(14;18)(q32;q21) translocation involving the bcl-2 gene and the amplification of the c-rel locus on chromosome 2p are detected exclusively in GCB-like DLBCL; 2) the mutational machinery introducing somatic mutations into Ig genes is active in all GCB-like DLBCL but not in the majority of ABC-like DLBCL tumors, and 3) the ABC-like DLBCL cell lines demonstrate high expression of NF-κB target genes and have constitutive activity of I-κB kinase complex (IKK) that is not observed in the GCB-like DLBCL cell lines. Inhibition of IKK by dominant negative forms of IκKβ was cytotoxic to ABC-like but not to GCB-like DLBCL cell lines. The latter study demonstrated that NF-κB pathway is a potential new therapeutic target in ABC-like DLBCL. However, specific pathways active in GCB-like DLBCL have not yet been characterized. Analysis of the relative prognostic contribution of the individual genes comprising the expression signatures defining these two DLBCL subgroups demonstrated that expression of only 48 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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