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 Liu, H, Savaraj, N, Priebe, W, and Lampidis, TJ. Hypoxia increases tumor cell sensitivity to glycolytic inhibitors: a strategy for solid tumor therapy (Model C). Biochemical Pharmacology 64:1745- 51, 2002. 2003 Feun, LG, O’Brien, C, Molina, E, Rodriguez, M, Jeffers, L, Schiff, ER, Marini, A, Savaraj, N, and Ardalan, B. Recombinant leukocyte interferon, doxorubicin, and 5FUDR in patients with hepatocellular carcinoma-A phase II trial. Journal of Cancer Research and Clinical Oncology 129:17- 20, 2003. Robles, C, Furst, AJ, Sriratana, P, Lai, S, Chua, L, Donnelly, E, Solomon, J, Sundaram, M, Feun, L, and Savaraj, N. Phase II study of vinorelbine with low dose prednisone in the treatment of hormone-refractory metastatic prostate cancer. Oncology Report 10:885-89, 2003. Savaraj, N, Wu, C, Wangpaichitr, M, Kuo, MT, Lampidis, TJ, Robles, C, Furst, AJ, and Feun, LG. Overexpression of mutated MRP4 in cisplatin resistant small cell lung cancer cell line: Collateral sensitivity to azidothymidine. International Journal of Oncology 23:173-9, 2003. Hu, YP, Haq, B, Carraway, KL, Savaraj, N, and Lampidis, TJ. Multidrug resistance correlates with overexpression of Muc4 but inversely with P-glycoprotein and multidrug resistance related protein in transfected human melanoma cells. Biochemical Pharmacology 65:1419-25, 2003. RAKESH SINGAL, M.D. Associate Professor of Medicine DESCRIPTION OF RESEARCH Dr. Singal’s research focuses on the mechanisms that inactivate certain tumor-suppressor genes in prostate cancer. A common mode of such inactivation involves a modification (methylation) in DNA. By understanding how genes are silenced, treatments can be developed to activate them and thereby prevent the development and/ or progression of prostate cancer. Researchers in Dr. Singal’s laboratory also are studying methylation of selected genes as a diagnostic and prognostic marker in prostate cancer. The present screening techniques for prostate cancer are very inefficient, and two out of three patients undergo prostate biopsy to detect cancer unnecessarily. Cancer patients often have a small amount of DNA circulating in their serum, thought to be released from the cancer cells. Dr. Singal’s laboratory has shown that certain methylated genes are present at a substantially higher percentage in prostate cancer tissue compared to benign prostatic conditions. Researchers are investigating if these methylated genes can be detected in serum DNA in patients with prostate cancer. If so, this test can be used as a part of prostate cancer screening, saving unnecessary prostate biopsies. DNA methylation plays a role during development by regulating gene expression. Another project in Dr. Singal’s laboratory focuses on understanding the role of methylation in regulating the expression of genes responsible for hemoglobin synthesis. Understanding the contribution of methylation to globin gene expression and the mechanisms involved will lead to the development of safe and effective therapies for globin gene disorders like thalassemia and sickle cell anemia. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 57
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 SELECTED PUBLICATIONS 2002 Singal, R, vanWert, JM, and Ferdinand, L Jr. Methylation of alpha-type embryonic globin gene alpha pi represses transcription in primary erythroid cells. Blood 100:4217-22, 2002. Singal, R, Wang, SZ, Sargent, T, Zhu, SZ, and Ginder, GD. Methylation of promoter proximal transcribed sequences of an embryonic globin gene inhibits transcription in primary erythroid cells and promotes formation of a cell type-specific methyl cytosine binding complex. Journal of Biological Chemistry 277:1897-1905, 2002. Noss, KR, Singal, R, and Grimes, SR. Methylation state of the prostate specific membrane antigen (PSMA) CpG island in prostate cancer cell lines. Anticancer Research 22:1505-11, 2002. 2003 Yaturu, S, Harrara, E, Nopajaroonsri, C, Singal, R, and Gill, S. Gynecomastia attributable to human chorionic gonadotropin-secreting giant cell carcinoma of lung. Endocrinology Practices 9:233-35, 2003. JOYCE M. SLINGERLAND, M.D., PH.D., F.P.R.C.(C) Professor of Medicine DESCRIPTION OF RESEARCH Dr. Slingerland’s research investigates how cancers escape negative growth controls. Following her discovery of a key inhibitor of cell cycle progression, p27, Dr. Slingerland and her colleagues went on to demonstrate that p27 levels are reduced in up to 60 percent of common human cancers (breast, prostate, lung, ovarian, and others), in association with poor patient prognosis. Dr. Slingerland showed that the therapeutic effect of antiestrogens in breast cancer requires the cyclin-dependent kinase (cdk) inhibitors p21 and p27 to mediate growth arrest. Oncogenic activation of mitogenic signaling via the mitogenactivated protein kinase (MAPK) pathway deregulates p27 function, causing tamoxifen resistance in breast cancer. She provided key insights demonstrating the role of cell cycle inhibitors p15 and p27 as mediators of G1 arrest by transforming growth factor-beta (TGF-β) and demonstrated that cancer cells lose responsiveness to this growth inhibitory cytokine through loss or deregulation of p27. In a recent publication, her laboratory demonstrated that checkpoint loss during cancer progression makes p27 an essential mediator of arrest. They also showed that functional inactivation of p27 in human cancers can either occur through accelerated p27 degradation or through altered p27 phosphorylation leading to p27 mislocalization. The laboratory recently showed that activation of mitogenic signaling via the receptor tyrosine kinases and the phosphoinositol 3’ kinase pathway alters p27 phosphorylation and function and the protein accumulates in the cytoplasm away from its targets in the nucleus. This work links oncogene activation with loss or inactivation of the cell cycle inhibitor, p27, elucidating a major mechanism of loss of growth control in cancer progression. Dr. Slingerland’s laboratory also is investigating the cause of aggressive estrogen receptor negative (ER-) breast cancers. Her group has found that oncogenic receptor tyrosine kinase and cSrc activation may not only activate mitogenic signaling leading to aggressive proliferation, but also lead to loss of detectable ER protein in ER negative (ER-) breast cancers. One third of newly diagnosed breast cancers are ER- and have a poor prognosis. Investigation of the mechanisms underlying the loss of ER expression showed that all of 70 primary ER- breast cancers expressed ER mRNA. Src or proteasome inhibition increased ER levels, and Src transfection stimulated both ligand activated ER transcriptional activity and ER proteolysis. Cotransfection of Her2 and Src reduced ER levels further. ER- primary breast cancers and cell lines showed increased Src activity compared to ER+ cancers and cell lines, and 58 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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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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