Targeted Therapy for Burkitt Lymphoma in Resource Poor Settings

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Burkitt lymphoma (BL) is particularly common in developing countries but differs from histologically similar tumors that occur in affluent nations. Sporadic and pediatric BLs seen in the US rarely contain EBV however, BLs in African populations are highly associated with the gamma herpes virus. Our studies indicate that the presence of EBV in lymphomas represents a selective target that can be exploited as a form of therapy. These findings have important implications and suggest that EBV associated BLs should be treated differently from viral negative tumors. Most new therapies for aggressive or relapsed B cell lymphomas are based upon intensive chemotherapeutic regimens, expensive modalities or experimental approaches (gene therapy, cytotoxic T cell infusion) that are difficult to implement in resource poor settings and unlikely to be applicable in patients with the endemic or HIV associated forms of the disease. We have demonstrated that primary HIV/EBV associated BLs are susceptible to zidovudine (AZT) mediated inhibition of Nuclear Factor Kappa B (NF-kB) and apoptosis. Suppression of NF-kB in EBV lymphomas exerts a unique and potent dual anti-tumor effect by both blocking a vital survival factor and inducing the EBV gene expression including viral thymidine kinase (vTK), which phosphorylates the thymidine analogue, AZT. Our preliminary data indicates that some primary unmanipulated Burkitt lymphomas express a lytic component and therefore should be highly sensitive to AZT. The use of the antiretroviral AZT, as an anticancer agent, is particularly desirable in patients with HIV and EBV associated lymphoma. We hypothesize that BLs that express a Type I latency pattern of EBV will be uniquely sensitive to lytic induction therapy via disruption of NF-kB whereas Type II and III Latent Membrane Protein 1 (LMP-1) positive tumors will require more potent suppression of the transcription factor or application of agents that induce the viral lytic program. Functional properties based upon latency, NF-kB expression and sensitivity to viral reactivation may be applied to EBV+BL. In order to investigate this we will investigate the molecular epidemiology and pathogenesis of primary tumors and prospectively analyze lymphomas derived from patients with EBV+ forms of BL. Knowledge gained from this pre-clinical study will have significance towards the development of targeted antiviral based therapies for these very common tumors. We have established collaborators in Brazil as well as outstanding on site infrastructure that will facilitate these studies. Our long term goal is to develop a targeted, efficacious, antiviral-based therapy for EBV (HIV) associated lymphoma that is applicable in developing nations.