Small molecule inhibitors show treatment potential for EBV-associated cancers
Researchers at The Wistar Institute have created a drug candidate for cancers associated with Epstein-Barr Virus (EBV), the virus that causes infectious mononucleosis. In a study published in Science Translational Medicine, they described inhibitors of an EBV protein called Epstein-Barr Nuclear Antigen 1 (EBNA1), showing efficacy in preclinical models.
More than 90% of adults are infected with EBV worldwide. The virus establishes life-long, latent infection in B lymphocytes, which is, in rare cases, associated with development of different cancer types, including Burkitt's lymphoma, nasopharyngeal carcinoma (NPC) and Hodgkin's lymphoma. EBNA1 is a DNA-binding protein critical for virus replication and for continuous proliferation of infected cells.
"EBNA1 is found in all EBV-associated tumors and does not look like any other protein in the human body," said Paul M. Lieberman, Ph.D., Hilary Koprowski, M.D., Endowed Professor, leader of the Gene Expression & Regulation Program at Wistar, and corresponding author on the study. "These characteristics, along with the protein's particular structure, make EBNA1 a very attractive therapeutic target."
Based on the 3-D structure of the protein, Lieberman and colleagues created a class of small molecule inhibitors of EBNA1 that block its ability to bind to DNA, as confirmed in EBV-infected NPC cells.
The efficacy of these inhibitors was tested in vivo in relevant mouse models of EBV-associated cancers, established by transplanting tumor cells or patient-derived tumor samples into immunocompromised mice. Researchers observed a dramatic reduction in tumor growth in all conditions tested. The tumor growth inhibition was greater than that achieved with gamma irradiation or chemotherapy, which are the standard-of-care treatments for NPC patients.
"It has taken the lab nearly a decade to go from concept to identifying a clinical candidate," said Troy E. Messick, Ph.D., first and co-corresponding author on the study and senior staff scientist in the Lieberman Lab. "We are excited about the activity of these inhibitors in a number of preclinical studies and look forward to the next steps of development."
Pharmacological inhibition of EBNA1 had profound effects on gene expression of both EBV and host-cell genes, which correlated with substantial decrease in EBV DNA copy number and suppression of EBV-driven tumor promoting pathways.
Importantly, tests showed a favorable pharmacological profile and little to no evidence of drug resistance after prolonged treatment.