Bernasconi
Fakultäten » Medizinische Fakultät » Kinderspital Zürich: Medizinische Klinik » Infektiologie, Abteilung » Prof. Dr. David Nadal » Bernasconi
Completed research project
| Title / Titel | Switching of latent to lytic EBV infection to specifically kill cancer cells | ||
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| Abstract (PDF, 14 KB) | |||
| Summary / Zusammenfassung | Epstein-Barr virus (EBV) is associated with many cancers including Burkitt’s lymphoma, other non-Hodgkin's lymphomas, Hodgkin's lymphoma, nasopharyngeal carcinoma, and lymphomas in the increasing population of organ transplant recipients and subjects infected with the human immunodeficiency virus. EBV, which is present in these cancers in a latent form, has developed ways to inactivate the cellular apoptotic machinery. The mechanisms mediating this inactivation have been extensively characterized. Nevertheless, virtually nothing is known about the molecular mechanisms regulating cellular survival when EBV is forced to switch from latent to lytic infection, The very presence of EBV in cancer cells but only in a minute fraction of normal healthy cells has suggested the development of EBV-targeted therapies with the aim to specifically remove EBV- associated cancer cells, while sparing healthy and bystander cells. One approach is the switching from latent to lytic EBV infection. In vitro, this can be initiated by a variety of agents and by cross-linking the immunoglobulin of the B-cell receptor on EBV-harboring cells. The degree of activation of switching, however, is very variable and the efficiency is still too low to justify therapeutic interventions in vivo.The key event of activation of lytic EBV infection is expression of the BZLF1 gene product, the transcription factor Zta, with subsequent activation of down-stream targets, eventually leading to virus production and cell lysis. Single steps of this process have been extensively analyzed, but the global picture is incomplete. We hypothesize that the killing of EBV-associated cancer cells by interfering with pathways responding to Zta. Therefore, we propose to identify downstream molecular targets of Zta which contribute to cellular survival upon switch from latent to lytic EBV infection. Moreover, we will establish a fluorescent cellular screening system, to identify molecular compounds that are able to activate with increased efficiency the BZLF1 promoter Zp transcription in malignant B-cells with the goal to optimize killing of EBV-harboring cancer cells by switching of latent to lytic EBV infection. We will be using the Burkitt’s lymphoma cell line Akata as a paradigm for induction of apoptosis in a p53-negative cellular background and of switching to lytic EBV infection in malignant cells. |
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| Keywords / Suchbegriffe | Epstein-Barr virus, lytic infection, lymphoma, Burkitt, treatment | ||
| Project leadership and contacts / Projektleitung und Kontakte |
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| Funding source(s) / Unterstützt durch |
Foundation Edoardo R., Giovanni, Giuseppe und Chiarina Sassella-Stiftung |
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| Duration of Project / Projektdauer | Jan 2007 to Dec 2007 |