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 the ER protein half-life was reduced in ERbreast cancer lines. These data support a model in which Her2 and cSrc cooperate with liganded ER to promote both ER dependent transcription and transcription linked ER proteolysis. SELECTED PUBLICATIONS 2002 Donovan, JC, Rothenstein, JM, and Slingerland, JM. Non-malignant and tumor-derived cells differ in their requirement for p27Kip1 in transforming growth factor-beta-mediated G1 arrest. Journal of Biological Chemistry 277:41686-92, 2002. Lian, J, Zubovitz, J, Petrocelli, T, Kotchetkov, R, Connor, MK, Han, K, Lee, JH, Ciarallo, S, Catzavelos, C, Beniston R, Franssen, E, and Slingerland, JM . PKB/Akt phosphorylates p27, impairs nuclear import of p27 and opposes p27- mediated G1 arrest. Nature Medicine 8:1153-60, 2002. Ciarallo, S, Subramaniam, V, Hung, W, Lee, JH, Kotchetkov, R, Sandhu, C, Milic, A, and Slingerland, JM . Altered p27(Kip1) phosphorylation, localization, and function in human epithelial cells resistant to transforming growth factor beta-mediated G(1) arrest. Molecular and Cellular Biology 22:2993-3002, 2002. 2003 Connor, MK, Kotchetkov, R, Cariou, S, Resch, A, Lupetti, R, Beniston, RG, Melchior, F, Hengst, L, and Slingerland, JM . CRM1/Ranmediated nuclear export of p27(Kip1) involves a nuclear export signal and links p27 export and proteolysis. Molecular Biology of the Cell 14:201-13, 2003. Liang, J and Slingerland, JM . Multiple Roles of the PI3K/PKB (Akt) Pathway in cell cycle progression. Cell Cycle 2:339-45, 2003. MARK S. SOLOWAY, M.D. Professor and Chairman of Urology DESCRIPTION OF RESEARCH Much of the work in the University of Miami’s department of Urology is devoted to better understanding the role of surgery in treating prostate, bladder, and kidney cancers. The department has established a rather unique database of more than 1,300 men who have had radical prostatectomy performed by one surgeon and their pathology has been read by one pathologist. Through the efforts of devoted researchers, they have reported on the relationship between a number of clinical and pathologic risk factors, e.g., positive surgical margin location, seminal vesicle invasion, and risk of relapse. This is critical when counseling patients regarding diagnosis, follow-up schedule and, most importantly, the need and type of additional treatment. Researchers in Dr. Soloway’s laboratory have introduced the concept of local anesthesia for prostate biopsies. This has the potential to benefit more than 500,000 men annually in the United States who undergo this otherwise rather painful procedure. More than 13 randomized studies confirm the researchers’ observation of the benefit of a periprostatic nerve block prior to ultrasound guided prostate biopsies. In an effort to minimize the morbidity of radical retropubic prostatectomy, Dr. Soloway has taken steps to enhance recovery without sacrificing cancer control. To this end, he has reported his results with nerve sparing, the omission of a pelvic drain, and the use of a cell saver to obviate the need for an allogeneic transfusion. In collaboration with Gaetano Ciancio, M.D., professor of Surgery and Urology, they have carefully detailed their surgical approach to large kidney tumors. They have adapted techniques developed for liver transplantation to reduce the morbidity and mortality related to surgery of large renal tumors, many of which involve extension into the vena cava. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 59
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 Lastly, Dr. Soloway’s interest in bladder cancer continues. He has published the first article detailing the growth pattern of low-grade bladder tumors. Using a cohort of patients with lowgrade Ta tumors who were observed by periodic endoscopy, they were able to emphasize the safety of carefully monitoring such tumors to obviate the morbidity and cost of frequent outpatient surgery. 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. 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 Simon, MA, Lokeshwar, VB, and Soloway, MS. Current bladder cancer tests: unnecessary or beneficial? Critical Reviews in Oncology/Hematology 47:91-107, 2003. Posey, JT, Soloway, MS, Ekici, S, Sofer, M, Civantos, F, Duncan, RC, and Lokeshwar, VB. Evaluation of the prognostic potential of hyaluronic acid and hyaluronidase (HYAL1) for prostate cancer. Cancer Research 63:2638-44, 2003. SHOU-CHING TANG, M.D., PH.D. Associate Professor of Medicine DESCRIPTION OF RESEARCH BAG-1 is a recently identified anti-apoptotic protein that binds to Bcl-2, hepatocyte, and platelet-derived growth factor receptors, enhancing their inhibition of apoptosis. It also binds to heat shock proteins, RAF-1 serine/threonine kinase, and hormone receptors and modulates their functions. Researchers in Dr. Tang’s laboratory detected the presence of one new BAG-1 isoform, p29. They showed that the four BAG-1 isoforms are localized differentially in subcellular compartments and in various tissues, suggesting that they perform different functions. They recently demonstrated that each BAG-1 isoform has a differing ability to inhibit apoptosis induced by various apoptosis-inducing agents. On the other hand, antisense against BAG-1 sensitized cells to apoptosis was induced by various chemotherapeutic agents. More significantly, these researchers observed the overexpression of BAG-1 in the majority of breast and lung cancer patients and its prognostic value. In addition, they observed the coexpression of BAG-1 with Bcl-2, p53, and estrogen receptor/progesterone receptor (ER/PR) in breast cancer tissues. They have isolated the BAG-1 promoter region and noted its up-regulation by the mutant p53. The laboratory also has raised monoclonal antibodies against individual BAG-1 isoforms, allowing for clinical correlation of BAG-1 expression and disease course. Current research at the basic molecular biology level involves the study of BAG-1 expression control and its interaction with other cellular proteins, including Bcl-2, ER/PR, and hsp to explore how BAG-1 inhibits apoptosis. At the clinical research level, research involves the development of BAG- 1 Mab and antisense in the prognosis and prediction to treatment response in a variety of solid tumors. 60 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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G L O S S A R Y IFN—interferon IL
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