VIRGO: Studying a VIRal Gpcr in Oncogenesis

ended

The Epstein–Barr virus (EBV) is widespread in all human communities. While most people carry EBV as a life-long asymptomatic infection, in some people, EBV contributes to malignant transformation and is responsible for ~200,000 new cancer cases/year. Small molecule inhibitors targeting viral proteins could be an effective option to treat people with EBV-associated cancers. However, no such drugs exists which in part reflects the limited repertoire of targetable virus proteins present in EBV-driven cancers. Recently, the Experienced Researcher (ER) has shown that the tumour cells of EBV-associated cancers such as Burkitt lymphoma (BL), express the EBV-encoded BILF1, a constitutively active G-protein coupled receptor (GPCR). Furthermore, preliminary data by the ER indicate that BILF1 partially recapitulates the aberrant transcriptional programme of BL and is likely to do so through activation of oncogenic cell signalling pathways that include AKT-mTOR. These data suggest that BILF1 could be a realistic therapeutic target, raising the possibility of advancing the development of anti-viral drugs to treat EBV-related tumours; GPCRs are the most successful class of drug target for the treatment of human disorders and are emerging as anti-cancer targets. In this project the ER will harness new models of B cell lymphomagenesis available in the host laboratory to: 1) Explore the role of BILF1in the transformation of germinal centre B cells; the progenitors of BL; 2) Identify how BILF1 contributes to the established phenotype of BL cells; and 3) Link these phenotypes to pathological features of the primary tumour and to patient response to therapy. Thus, the Fellowship will significantly advance knowledge of the mechanisms of EBV-mediated oncogenesis, in turn paving the way for the development of new EBV-targeted small molecule drugs. The ER will emerge from this project with a new advanced skill-set and the capability to launch her own high level scientific research.