Developing drugs for the treatment of Epstein-Barr virus-associated cancers using more widespread targets

Epstein-Barr virus (EBV) causes 200,000 lymphomas and carcinomas world-wide each year.

These include Burkitt’s lymphoma (BL), Hodgkin’s lymphoma, diffuse large B cell lymphoma, post-transplant lymphoproliferative disease, nasopharyngeal carcinoma (NPC) and gastric carcinoma.

The continued presence of EBV in tumour cells provides an excellent opportunity to develop anti-EBV therapies to specifically target these cancers and leave normal cells unscathed.

However, to date no anti-EBV drugs are available and patients are treated with the same toxic and invasive chemotherapy, radiotherapy or surgical regimens as patients with tumours of non-viral origin. This project addresses this unmet need.

All EBV-positive tumour cells produce the viral protein EBNA1 as it is required for the survival of the virus genome and the host cell, making it an excellent target for anti-EBV therapeutics. Screening for compounds that block EBNA1 activity performed thus far have used one EBV reference strain.

New data shows that variants of EBNA1 distinct from the reference strain are more representative of globally-circulating strains.

This project uses EBNA1 from the EBV reference strain and a widespread newly-identified strain in a fragment-based screen to identify hit matter for drug discovery. Our aim is to identify hits that target both strains, or the most widespread strain if not possible.

We will then use medicinal chemistry approaches to produce analogues with appropriate ligand-binding and drug-like properties to test in in vitro and cell-based assays for disruption of EBNA1 functions and specific inhibition of EBV-positive tumour cell growth.

We aim to identify a lead-like compound for onward studies to help reduce disease burden and provide targeted and kinder alternatives to current therapies.