Burkitt lymphoma (BL), the most common pediatric lymphoproliferative disease in developing nations, is highly associated with Epstein Barr virus (EBV). These virulent tumors can be cured with chemotherapy but relapsed or resistant disease is quite common and generally fatal. We hypothesize that the presence of EBV in the endemic form of BL can be used both to monitor response to therapy and as a therapeutic target. In our first aim we propose to study EBV viral load in BL patients enrolled on a therapeutic protocol. We will determine whether EBV viral load correlates with response to therapy or conversely with relapsing or resistant disease. We will also investigate the effect of chemotherapy on viral reactivation. We further hypothesize that the antiviral agent azidothymidine (AZT) induces apoptosis in EBV+ BL through a unique, targeted mechanism: suppression of NF-kappaB and disruption of viral latency. This results in phosphorylation of AZT by viral kinases and apoptosis. Therefore, AZT is essentially an inexpensive form of gene therapy that exploits the presence of EBV. There is no effective therapy for relapsed endemic type BLs.
In aim 2 we will conduct a trial of chemo/antiviral (AZT, hydrea) therapy for these patients. Commonly available chemotherapeutic agents are known to induce the EBV lytic cycle including viral thymidine kinase and thereby potentiate phosphorylation of AZT. Our group, comprised of pediatric and adult hematologists, virologists, research nurses and pathologists offers multidisciplinary expertise required for this translational study. Our collaborators, located at a unique site where viral lymphoproliferative diseases are commonly diagnosed, have excellent infrastructure in place to participate in this study. Data acquired through this project should be broadly applicable to high grade lymphomas that occur in Immune compromised individuals. These studies should lead to new, non-carcinogenic, abbreviated therapy that is applicable in developing nations for this common tumor.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112217-05
Application #
7935180
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Liddell Huppi, Rebecca
Project Start
2006-09-22
Project End
2012-07-31
Budget Start
2010-08-04
Budget End
2012-07-31
Support Year
5
Fiscal Year
2010
Total Cost
$236,524
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
052780918
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Bayraktar, Ulas Darda; Diaz, Luis A; Ashlock, Brittany et al. (2014) Zidovudine-based lytic-inducing chemotherapy for Epstein-Barr virus-related lymphomas. Leuk Lymphoma 55:786-94
Ramos, Juan-Carlos; Sin, Sang-Hoon; Staudt, Michelle R et al. (2012) Nuclear factor kappa B pathway associated biomarkers in AIDS defining malignancies. Int J Cancer 130:2728-33
Ramos, Juan Carlos; Lossos, Izidore S (2011) Newly emerging therapies targeting viral-related lymphomas. Curr Oncol Rep 13:416-26
Gualco, Gabriela; Weiss, Lawrence M; Harrington Jr, William J et al. (2010) BCL6, MUM1, and CD10 expression in mantle cell lymphoma. Appl Immunohistochem Mol Morphol 18:103-8
Gualco, Gabriela; Chioato, Lucimara; Harrington Jr, William J et al. (2009) Primary and secondary T-cell lymphomas of the breast: clinico-pathologic features of 11 cases. Appl Immunohistochem Mol Morphol 17:301-6
Gualco, Gabriela; Weiss, Lawrence M; Harrington Jr, William J et al. (2009) Nodal diffuse large B-cell lymphomas in children and adolescents: immunohistochemical expression patterns and c-MYC translocation in relation to clinical outcome. Am J Surg Pathol 33:1815-22
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
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

Showing the most recent 10 out of 11 publications