# Drugging EBNA1 to Treat EBV-Associated Cancers

> **NIH NIH R01** · WISTAR INSTITUTE · 2021 · $582,466

## Abstract

Project Summary
EBV latent infection is responsible for ~200,000 new cancers per year. To date, there are no EBV-
specific therapeutic agents that selectively and efficaciously treat EBV-positive tumors. All known
EBV tumors consistently express one viral nuclear protein, EBNA1, that is required for maintaining
the EBV genome and promoting infected cell survival. We have developed highly selective, drug-like
small molecules that bind EBNA1 and block its ability to bind DNA, maintain EBV genomes, and
promote host-cell survival. Here we propose to better understand the mechanism through which
disruption of EBNA1 DNA binding leads to tumor growth inhibition, and use this information to identify
rational combinatorial agents to enhance chemotherapeutic efficacy. We propose to enhance the
potency of the first generation EBNA1 inhibitors by attaching proteasome targeting molecules
(PROTACS) to selectively target EBNA1 for degradation. Finally, we will take advantage of new
mechanistic data revealing that EBNA1 functions as an OriP-specific endonuclease and resolvase.
We propose to develop new structure and mechanism-based inhibitors of EBNA1 that can increase
potency necessary for highly efficacious cancer therapy. By integrating these strategies to
understand the growth arrest response of EBNA1 inhibition (aim 1) to better develop rational
approaches for combinatorial therapies (aim 2) and develop next generation molecule with
structure/mechanism based drug design principles (aim 3), we will advance EBNA1 inhibitors for the
treatment of EBV-associated malignancies and related-diseases. We will test the overarching
hypothesis that EBNA1 is an effective target for small molecule inhibitors to treat EBV
cancers. The major goal of this proposal is to understand the tumor cell response to EBNA1
inhibition and to enhance efficacy of EBNA1 inhibitors to treat EBV-associated cancers more
efficaciously. The team associated with this proposal has the unique expertise and strong
collaborative history to execute the aims of this proposal. Collectively, these investigations will
provide fundamental insights into how EBNA1 functions at the molecular level and will lay the
foundation for the development of new strategies to treat EBV cancers.

## Key facts

- **NIH application ID:** 10185459
- **Project number:** 1R01CA259171-01
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** PAUL M. LIEBERMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $582,466
- **Award type:** 1
- **Project period:** 2021-06-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10185459

## Citation

> US National Institutes of Health, RePORTER application 10185459, Drugging EBNA1 to Treat EBV-Associated Cancers (1R01CA259171-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10185459. Licensed CC0.

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