New Small Molecule Inhibitors Show Potential for Treatment of Epstein-Barr Virus-Associated Cancers
First-in-class pharmacological inhibitors of the EBNA1 viral protein are effective at inhibiting tumor growth in preclinical models.
Newswise — PHILADELPHIA — (March 6, 2019) — 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.
The Wistar Institute has granted an exclusive worldwide license for the development and commercialization of VK-2019, an EBNA1 inhibitor, to Cullinan Apollo Corp., a wholly owned subsidiary of Cullinan Oncology, LLC. Cullinan anticipates initiating enrollment in a global phase 1/2 clinical study in the second quarter of 2019.
Co-authors: Samantha S. Soldan, Julianna S. Deakyne, Kimberly A. Malecka, Lois Tolvinski, Donna H. Tran, and Benjamin R. Wassermann from Wistar. Garry R. Smith, Mark E. McDonnell, Yan Zhang, Venkata Velvadapu, and Allen B. Reitz from Fox Chase Chemical Diversity Center, Inc; A. Pieter J. van den Heuvel, Bai-Wei Gu and Joel A. Cassel from Vironika, LLC; Pierre Busson from Institut Gustave Roussy, France; and Edward R. Zartler from Quantum Tessera Consulting, LLC.
Work supported by: National Institutes of Health (NIH) grants R43AI079928, R43AI096588, R44AI096588, R01CA093606, R01DE017336, and T32 CA09171; and two Seeding Drug Discovery grants from Wellcome (WT096496/Z/11/Z). Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30CA010815.
Publication information: Structure-based design of small molecule inhibitors of EBNA1 DNA-binding blocks Epstein-Barr virus latent infection and tumor growth, Science Translational Medicine (2019). Advance online publication.
The Wistar Institute is an international leader in biomedical research with special expertise in cancer, immunology, infectious disease research, and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.