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 fusion protein targeting to xenogeneic (e.g., CEA, her2/neu) antigens, while preserving T-cell immune-effector functions. The B-cell deficient model also has demonstrated T-cell responses to tumor and may be better than those seen in the immunocompetent mouse. The laboratory is currently investigating the reasons for altered responses in the absence of B cells, and the possibility of applying this approach to clinically using antibody depletion of B cells with rituximab. Dr. Rosenblatt and his colleagues also have collaborated with the laboratory of Vicente Planelles, Ph.D., at the University of Utah, on developing several new approaches to HIV-1 gene therapy. These include the use of mutated tRNA LYS3 primers, which can anneal to the sequences other than primer-binding sequences on the HIV-1 genome, or tRNA LYS3 mutated in adenosine residue A58, which prevents normal methylation of the adenosine residue and disrupts proper termination of the nascent reverse transcript, thereby inhibiting completion of HIV-1 reverse transcription in model systems. Other investigations have centered on the effects of defective HIV-1 derived vectors on HIV-1 spread in culture. Recent experiments have demonstrated that efficient trafficking of defective HIV-1 vectors is observed in vitro following superinfection with wild type HIV-1 and that such trafficking results in a marked inhibition of wild type viral spread. SELECTED PUBLICATIONS 2002 Lancet, JE, Rosenblatt, JD , and Karp, JE. Farnesyltransferase inhibitors and myeloid malignancies: phase I evidence of Zarnestra activity in high-risk leukemias. Seminars in Hematology 39:31-35, 2002. Tolba, KA, Bowers, WJ, Muller, J, Housekneckt, V, Giuliano, RE, Federoff, HJ, and Rosenblatt, JD. Herpes simplex virus (HSV) amplicon-mediated codelivery of secondary lymphoid tissue chemokine and CD40L results in augmented antitumor activity. Cancer Research 62:6545-51, 2002. Rosenblatt, JD , Shin, SU, Nechustan, H, Yi, KH, and Tolba, K. Potential role of chemokines in immune therapy of cancer. Israel Medical Association Journal 4:1054-59, 2002. Tolba, KA, Bowers, WJ, Eling, DJ, Casey, AE, Kipps, TJ, Federoff, HJ, and Rosenblatt, JD . HSV amplicon-mediated delivery of LIGHT enhances the antigen-presenting capacity of chronic lymphocytic leukemia. Molecular Therapy 6:455- 63, 2002. Andela, VB, Rosenblatt, JD , Schwarz, EM, Puzas, EJ, O’Keefe, RJ, and Rosier, RN. Synergism of aminobisphosphonates and farnesyl transferase inhibitors on tumor metastasis. Clinical Orthopaedics 397:228-39, 2002. 2003 Khorana, AA, Rosenblatt, JD , Sahasrabudhe, DM, Evans, T, Ladrigan, M, Marquis, D, Rosell, K, Whiteside, T, Phillippe, S, Acres, B, Slos, P, Squiban, P, Ross, M, and Kendra, K. A phase I trial of immunotherapy with intratumoral adenovirus-interferon-gamma (TG1041) in patients with malignant melanoma. Cancer Gene Therapy 10:251-9, 2003. Andela, VB, Pirri, M, Schwarz, EM, Puzas, EJ, O’Keefe, RJ, Rosenblatt, JD, and Rosier, RN. The mevalonate synthesis pathway as a therapeutic target in cancer. (Review) Clinical Orthopaedics 415 (Supplement):S59-66, 2003. Liesveld, JL, Lancet, JE, Rosell, KE, Menon, A, Lu, C, McNair, C, Abboud, CN, and Rosenblatt, JD. Effects of the farnesyl transferase inhibitor R115777 on normal and leukemic hematopoiesis. Leukemia 17:1806-12, 2003. Rosenblatt, JD and Harrington, WJ Jr. Leukemia and myelopathy: the persistent mystery of pathogenesis by HTLV-I/II. Cancer Investigation 21:323-24, 2003. UM/Sylvester Comprehensive Cancer Center Scientific Report 2004 55
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 HIGHLIGHTS/DISCOVERIES • Developed novel antibody-chemokine and antibody-costimulatory ligand fusion proteins with dual function and preserved targeting capabilities. • Developed a novel strategy for gene therapy of HIV-1 using mutations introduced into the tRNA LYS3 primer. • Demonstrated the potential role for HSV amplicon vectors in gene therapy of malignancy, particularly CLL. • Demonstrated the use of trafficking and inhibition by defective HIV-1 as a novel approach to HIV-1 gene therapy. • Demonstrated the utility of combining chemokine delivery with costimulatory ligands in augmenting mouse response to tumors. NIRAMOL SAVARAJ, M.D. Adjunct Professor of Medicine DESCRIPTION OF RESEARCH Molecular Mechanism of Drug Resistance in Small Cell Lung Cancer Small cell lung cancer (SCLC) usually responds to chemotherapy, but relapse is inevitable. Although several new chemotherapeutic agents have shown activity in SCLC, salvage therapy is still poor. Research in Dr. Savaraj’s laboratory focuses on identifying the mechanisms of drug resistance in SCLC and developing approaches to overcome them. Since the combination of VP-16 and cisplatin is the most commonly used regimen in treating SCLC, the laboratory has studied the mechanism(s) of resistance of these two agents. They have established two pairs of cisplatin resistant sublines (SR-2 and BC), one VP-16 resistant subline (BV), one MRP1 (SCLCA), and one P- gp (SCLCR) resistant subline from two parental lines (SCLC1 and SCLCB). These cell lines were used to study the mechanism(s) of resistance in SCLC. Using cDNA subtraction and microarray, the laboratory has found that both cisplatin resistant cell lines overexpressed three families of cDNAs, the MMP family, DNA damage and repair proteins, and proteins involved in translation. The specific genes that were consistently elevated were elongation factor and ribosomal protein. Since rapamycin or its analog CCI-779 can inhibit translation of the mRNA encoding elongation factor, they have investigated whether these analogs could reverse cisplatin drug resistance. Dr. Savaraj and her colleagues found that all cell lines were sensitive to rapamycin and CCI-779 with the ID 50 ranged from 0.05-0.1µg/ ml. Furthermore, at 0.01µg/ml both drugs could also restore cisplatin sensitivity, and could completely restore VP-16 sensitivity in BV cell line. Neither rapamycin nor CCI-779 is able to reverse P-gp1 or MRP1 resistance. SELECTED PUBLICATIONS 2002 Feun, LG, Modiano, M, Lee, K, Mao, J, Marini, A, Savaraj, N, Plezia, P, Almassian, B, Colacino, E, Fischer, J, and MacDonald, S. Phase I and pharmacokinetic study of 3-aminopyridine-2- carboxaldehyde thiosemicarbazone (3-AP) using a single intravenous dose schedule. Cancer Chemotherapy and Pharmacology 50:223-29, 2002. Wangpaichitr, M, Landy, H, Wu, CJ, Feun, LG, Xu, R, Xu, J, and Savaraj, N. Procollagen-like protein as a molecular target in the treatment of primary brain tumor. ScientificWorldJournal. 2:125-26, 2002. Feun, LG, Savaraj, N, Hurley, J, and Marini, A. Phase II trial of Paclitaxel and Dacarbazine with filgrastim administration in advanced malignant melanoma. Cancer Investigation 20:357-61, 2002. 56 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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