A team of FSM researchers recently received a 6.7 percentile score on an RO1 by principal investigator Richard Longnecker, PhD, Professor of Microbiology-Immunology and co-investigators Leo Gordon, MD, Professor of Medicine; Andrew Evens, DO, Assistant Professor of Hematology-Oncology;  and Borko Jovanovic, PhD, Associate Professor of Preventive Medicine. This grant, focusing on development of drugs targeting Epstein-Barr virus (EBV) in EBV-associated blood cancers, came out of the Lymphoma SPORE application and represents the first grant that comes directly from FSM’s new lymphoma program. The lymphoma SPORE, if funded, would be the third SPORE at FSM, along with breast and prostate SPOREs. SPOREs (Specialized Programs of Research Excellence) are supported by the  National Center Institute.

Epstein-Barr virus is a herpesvirus that  infects approximately 95% of the human population and usually results in the benign, latent infection of memory B lymphocytes for the life of the host. Epstein-Barr virus  is unique, however, in that latent infection can lead to virus-associated malignancies such as Burkitt lymphoma (BL), Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), and nasopharyngeal carcinoma (NPC). The specific goals of this study are to identify drugs that will target Epstein-Barr virus (EBV) latent infections and EBV-associated hematologic cancers and proliferative disorders that occur in the human host.

Understanding EBV latent infection provides insight into the pathogenesis of EBV-associated disease and may lead to targeted therapies to prevent or treat EBV-associated malignancies. Latent membrane protein 2A (LMP2A) is an EBV protein expressed in latently infected B-lymphocytes and detected in EBV-associated malignancies. LMP2A alters and mimics normal B cell signaling pathways induced by the B cell receptor (BCR) to prevent apoptosis and prolong cell survival. LMP2A function is dependent on numerous cellular proteins including the Lyn and Syk protein tyrosine kinases (PTKs), and the Ras/PI3K/Akt pathway. The FSM investigators hypothesize that LMP2A is essential for EBV latency and EBV-associated pathogenesis by altering normal BCR function and activating intracellular pro-survival and anti-apoptotic pathways that block important cellular checkpoints such as Myc-induced apoptosis. Using a novel in vivo murine model of EBV latency developed in their laboratory and a novel in vitro methodology, Dr. Longnecker and his co-investigators will test pharmacological inhibitors of LMP2A-activated proteins. Many of these inhibitors are currently being tested and are in early stages of human trials for treatment of other diseases unrelated to EBV-associated disease.  Promising data using a murine transgenic model would provide important data to justify proposed human studies with EBV-related lymphomas. Finally, other targets may be identified in our proposed research that effectively target LMP2A function. Overall, the studies proposed will test the feasibility of LMP2A signaling inhibition and identify the most effective inhibitors. This work will provide a foundation for in vivo drug development studies and may lead to therapeutic options for EBV-associated cancers such as EBV-associated HL and NHL.