Therapy for lymphoproliferative disease in immunocompromised patients is problematic. These patients often have a poor response to cytotoxic agents that also worsens their underlying immunosuppression. Nonetheless, there are distinct pathophysiologic features of these tumors that may be exploited as therapeutic targets. These lymphomas are often associated with gamma herpesviruses and dependent upon constitutive expression of NF-kappaB. We have identified a novel, pro-apoptotic therapy for Humanherpes Virus Type 8 (HHV-8), Primary Effusion Lymphoma (PEL) and Epstein Barr Virus (EBV) lymphomas. Azidothymidine (AZT) and Interferon alpha induce death receptor ligand mediated apoptosis in PEL. This occurs through a potent activation of the ligand TRAIL mediated by interferon alpha coupled with suppression of NF-kappaB by AZT. We hypothesize that death receptor signaling is potentiated upon suppression of NF-kappaB dependent anti-apoptotic factors. NF-kappaB blockade is effected by the monophosphate form of AZT which is preferentially generated in HHV-8 and EBV associated lymphomas. We have demonstrated the effectiveness of antiviral therapy for gamma herpesvirus associated lymphomas in both animal models and patients. We propose to investigate the cellular and viral factors that mediate this apoptosis by 1) defining the signal transduction pathways induced by antivirals in herpesvirus lymphomas; 2) determining the role of cellular and viral proteins (such as vFlip) in NF-kappaB mediated blockade of death receptor mediated apoptosis; 3) investigating the role of viral thymidine kinase in the phosphorylation of antiviral thymidine analogues and the initiation of apoptosis and; 4) studying the anti-lymphoma effects of antivirals in a recently developed SCID mouse model. Development of a therapeutic strategy based on antiviral therapy would represent a targeted, biological approach to lymphomas in resource poor settings. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA082274-05
Application #
6734649
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Bhatia, Kishor
Project Start
2000-04-01
Project End
2008-03-31
Budget Start
2004-07-23
Budget End
2005-03-31
Support Year
5
Fiscal Year
2004
Total Cost
$301,059
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Miami
State
FL
Country
United States
Zip Code
33146
Gualco, Gabriela; Queiroga, Eduardo M; Weiss, Lawrence M et al. (2009) Frequent expression of multiple myeloma 1/interferon regulatory factor 4 in Burkitt lymphoma. Hum Pathol 40:565-71
Gualco, Gabriela; Chioato, Lucimara; Weiss, Lawrence M et al. (2009) Analysis of human T-cell lymphotropic virus in CD25+ anaplastic large cell lymphoma in children. Am J Clin Pathol 132:28-33
Xia, Tianli; O'Hara, Andrea; Araujo, Iguaracyra et al. (2008) EBV microRNAs in primary lymphomas and targeting of CXCL-11 by ebv-mir-BHRF1-3. Cancer Res 68:1436-42
Queiroga, Eduardo M; Gualco, Gabriela; Weiss, Lawrence M et al. (2008) Burkitt lymphoma in Brazil is characterized by geographically distinct clinicopathologic features. Am J Clin Pathol 130:946-56
Gualco, Gabriela; Weiss, Lawrence M; Bacchi, Carlos E (2008) Expression of p63 in anaplastic large cell lymphoma but not in classical Hodgkin's lymphoma. Hum Pathol 39:1505-10
Gualco, Gabriela; Bacchi, Carlos E (2008) B-cell and T-cell lymphomas of the breast: clinical--pathological features of 53 cases. Int J Surg Pathol 16:407-13
Queiroga, Eduardo M; Gualco, Gabriela; Chioato, Lucimara et al. (2008) Viral studies in burkitt lymphoma: association with Epstein-Barr virus but not HHV-8. Am J Clin Pathol 130:186-92
Gualco, Gabriela; van den Berg, Anke; Koopmans, Sicco et al. (2008) Autoimmune lymphoproliferative syndrome in a patient with a new minimal deletion in the death domain of the FAS gene. Hum Pathol 39:137-41
Minhas, Veenu; Crosby, Lynsey N; Crabtree, Kay L et al. (2008) Development of an immunofluorescence assay using recombinant proteins expressed in insect cells to screen and confirm presence of human herpesvirus 8-specific antibodies. Clin Vaccine Immunol 15:1259-64
Ramos, Juan Carlos; Ruiz Jr, Phillip; Ratner, Lee et al. (2007) IRF-4 and c-Rel expression in antiviral-resistant adult T-cell leukemia/lymphoma. Blood 109:3060-8

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