SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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V I R A L O N C O L O G Y P R O G R A M vide targets for therapeutic intervention to control infection and decrease proviral load. HTLV-I encodes a trans-activating protein, Tax, which is responsible for the oncogenic properties of HTLV-I. Tax activates numerous cellular signaling cascades, including NF-κB and CREB/ ATF, resulting in global changes in gene expression. Tax regulates the expression of a multitude of cellular genes that control T-cell activation, proliferation and apoptosis. Another goal of Dr. Harhaj’s laboratory is to delineate the mechanisms utilized by Tax to activate cellular signaling pathways, such as NF-κB, which are essential for Tax-mediated immortalization of T cells. Toward this end, identification of cellular proteins that interact with Tax may shed light on strategies used by Tax to constitutively activate NF-κB and mediate T-cell oncogenesis. SELECTED PUBLICATIONS 2003 Barmak, K, Harhaj, EW, and Wigdahl, B. Mediators of central nervous system damage during the progression of HTLV-I-associated myelopathy/tropical spastic paraparesis. Journal of NeuroVirology 9:522-9, 2003. Barmak, K, Harhaj, EW Grant, C, Alefantis, T, and Wigdahl, B. Human T cell leukemia virus type I-induced disease: pathways to cancer and neurodegeneration. Virology 308:1-12, 2003. Alefantis, T, Barmak, K, Harhaj, EW, Grant, C, and Wigdahl, B. Characterization of a nuclear export signal within the human T cell leukemia virus type I transactivator protein Tax. Journal of Biological Chemistry 278:21814-22, 2003. WILLIAM J. HARRINGTON, JR., M.D. Professor of Medicine DESCRIPTION OF RESEARCH Dr. Harrington's laboratory efforts center on understanding the mechanisms of antiviralmediated apoptosis of viral-mediated malignancies. His team found that interferon (IFN) potently induces death receptor ligands in certain unique viral-mediated lymphomas. This had led to a novel therapeutic approach for these deadly tumors. Epstein-Barr virus (EBV)-related Burkitts (BL) and primary central nervous system (CNS) lymphoma, human herpes virus-type 8 (HHV-8)- associated primary effusion lymphoma (PEL), and human T lymphotropic virus-type I (HTLV- I)-associated adult T-cell leukemia (ATL) are all refractory to conventional chemotherapy yet remarkably sensitive to antiviral therapy. Clinical trials have been designed and implemented that exploit this phenomenon. Their AIDS-related brain lymphoma study is now a national trial and is run through the NCI cooperative group, the Aids Malignancy Consortium (AMC). The three principal projects currently underway include: • Mapping the apoptotic pathways induced in viral-associated lymphomas. Their work has demonstrated that IFNα induced the soluble death receptor ligand TRAIL, which when combined with AZT, indicates a FADD-dependent suicide program in gamma herpes virus lymphomas. Signal transduction deficits in IFNα and pathways in resistant tumors also are being studied. • Studying the signaling components involved in constitutive activation of NF-κB in all forms of viral-mediated non-Hodgkin's lymphoma (NHL). Their data demonstrate specific activation pathways that may serve as targets for future therapeutic agents. • Elucidating the mechanism whereby AZT inhibits NF-κB in EBV+ endemic BL. New data demonstrate that this mechanism is highly specific and occurs through interruption of UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 139
V I R A L O N C O L O G Y P R O G R A M lymphotoxin beta-mediated activation of NF-kB. AZT appears to be a targeted form of therapy particularly active in type 1 latency BL cells. Dr. Harrington recently has received NCI funding to study this mechanism in primary endemic BL cells from patients seen at the National Cancer Institute of Brazil (INCA). This also will be translated to a clinical trial for refractory EBV+ B1. They have received a major commitment from GlaxoSmithKline to provide parenteral AZT. This will be used as part of a protocol to treat patients at the INCA. SELECTED PUBLICATIONS 2002 Tulpule, A, Groopman, J, Saville, MW, Harrington, WJ Jr , Friedman-Kien, A, Espina, BM, Garces, C, Mantelle, L, Mettinger, K, Scadden, DT, and Gill, PS. Multicenter trial of low-dose paclitaxel in patients with advanced AIDS-related Kaposi sarcoma. Cancer 95:147- 54, 2002. 2003 Ghosh, SK, Wood, C, Boise, LH, Mian, AM, Deyev, VV, Feuer, G, Toomey, NL, Shank, NC, Cabral, L, Barber, GN, and Harrington, WJ Jr . Potentiation of TRAIL-induced apoptosis in primary effusion lymphoma through azidothymidine-mediated inhibition of NFkappa B. Blood 101:2321-7, 2003. Rosenblatt, J and Harrington, WJ Jr . Leukemia and myelopathy: the persistent mystery of pathogenesis by HTLV-I/II. Cancer Investigation 21:323-4, 2003. Schultz, DR and Harrington, WJ Jr . Apoptosis: programmed cell death at a molecular level. Seminars in Arthritis and Rheumatism 32:345- 69, 2003. ANTERO G. SO, M.D., PH.D. Professor of Medicine DESCRIPTION OF RESEARCH Dr. So and Kathleen M. Downey, Ph.D., are studying the molecular mechanism by which normal cells regulate proliferation during the cell cycle and how this is altered in cancer cells. The major focus of these studies is DNA polymerase delta, the principal mammalian DNA polymerase required for replication of chromosomal DNA and involved in several major DNA repair pathways. DNA polymerase delta was the first eukaryotic DNA polymerase found to have an intrinsic proofreading 3’ to 5’ exonuclease activity and therefore capable of editing errors made during DNA synthesis. The importance of this proofreading activity in DNA replication was recently shown by a report that inactivation of the exonuclease activity of DNA polymerase delta in mice resulted in a recessive mutator phenotype characterized by a high incidence of epithelial (carcinoma) and mesenchymal (lymphomas and sarcomas) cancers. Current research emphasizes the elucidation of the molecular mechanism of regulation of DNA polymerase delta activity by its processivity factor, the proliferating cell nuclear antigen (PCNA), and the identification of new proteins that regulate DNA polymerase delta activity. 140 UM/Sylvester Comprehensive Cancer Center Scientific Report 2004
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SCIENTIFIC REPORT 2004 - Sylvester Comprehensive Cancer Center

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