UNC Lineberger Comprehensive Cancer Center
Project Term: July 1, 2023 - June 30, 2026
This work focuses on characterizing the role of FAM72A in EBV-driven B cell tumorigenesis. This protein is upregulated by EBV during the transformation of B cells and overexpressed in many hematologic cancers. Using a combination of in vitro and in vivo EBV transformation models, high-throughput drug screens, and structural analysis we aim to find small molecules inhibitors that target FAM72A and determine if these drugs can prevent or hinder EBV-associated B cell malignancies.
In the U.S. over 180,000 new cases of blood cancers are found each year and about half of these are B-cell non-Hodgkin lymphomas or leukemias (B-NHL). Annually about 25,000 deaths occur due to these diseases. Most B-NHLs originate during B cell maturation including the more aggressive and fast-growing B-NHLs associated with Epstein-barr virus (EBV). EBV is the most prevalent human virus infecting ~95% of the population. Most infected individuals remain asymptomatic throughout their lifetime as the virus typically establishes life-long latency in memory B cells. However, while latent, EBV can facilitate the transformation of B cells to various malignancies including Burkitt’s lymphoma (BL), classic Hodgkin’s lymphoma, post-transplant B-lymphoproliferative disease, diffused large B cell lymphoma (DLBCL), primary central nervous system lymphoma, plasmablastic lymphoma, and primary effusion lymphoma. EBV-positive BLs are particularly aggressive and have a high incidence rate in children of sub-Saharan Africa. This endemic BL is associated with EBV and malaria and accounts for 50-75% of childhood cancers in some countries. EBV-positive DLBCL’s are more aggressive and fast-growing than non-viral tumors. Consequently, the prognosis of EBV-associated DLBCL is significantly worse.
My research focuses on characterizing the role of an oncogenic protein called FAM72A in B cell cancers. This protein promotes mutations and DNA instability in B cells and is found overexpressed in aggressive B-NHLs and EBV transformed B cells. Using human primary B cells and a DLBCL mouse model, we will determine the role FAM72A plays in B cell cancer disease formation and tumor progression. Our mouse model uses EBV-infected human B cells which form DLBCL tumors in mice reminiscent of the human disease. Using cryogenic technology, we will solve the structure of FAM72A with its binding partners to inform design of inhibitors that will disrupt its pathogenesis. Key indicators of success for this work will be clearly defining the role of FAM72A in B cell transformation then identifying several drugs to inhibit FAM72A’s pathogenesis in B-NHL cell models. Finally, if tumors in our mouse model respond to drugs found in this study, we will have successfully identified a new druggable target for the treatment of the aggressive EBV-associated B-NHLs. The relevant next step will be to extend these therapies to non-viral B-NHLs with FAM72A overexpression and other EBV-associated blood cancers.