# Epigenomic Drivers of EBV Epithelial Cancers

> **NIH NIH P01** · WISTAR INSTITUTE · 2024 · $433,626

## Abstract

PROJECT 1 – PROJECT SUMMARY
The long-term goal of this project is to determine how EBV establishes an oncogenic latent epigenome in EBV-
associated epithelial cancers and to leverage this information to develop new therapeutic strategies to target
EBV latent infection in epithelial cancers. All EBV cancers share the common feature of maintaining latent viral
genomes that express a restricted subset of viral oncogenes. EBV epithelial cancers also have the distinguishing
feature of CpG Island Methylation Phenotype (CIMP). The role of EBV latent infection in driving CIMP, and the
role of CIMP in regulating oncogenic EBV latency are not fully elucidated, but critical for understanding EBV
carcinogenesis. In Aim 1, we propose to investigate how EBV latent infection promotes CIMP. We will test the
specific hypothesis that EBNA1-driven episome maintenance induces a PARP1-dependent DNA-damage
response that drives CIMP. In collaboration with Project 2, we will investigate the role of PARP1 and UHRF1 in
the formation of site-specific viral and host DNA methylation. In collaboration with Project 3, we will explore the
role of PI3K activation in controlling replication stress in epithelial cancers. In Aim 2, we will test the hypothesis
that CIMP and other somatic changes, such as PI3K and ARID1A mutations, facilitate the formation of a viral
type II latency. In collaboration with Project 2, we will examine the role of CTCF and CIMP on EBV 3D
conformation. With Project 3, we will investigate how metabolic changes favor establishment of type II latency
in epithelial cancers. Finally, we will work in collaboration with Projects 2, 3 and all Cores to identify new
therapeutic approaches to treat EBV(+) epithelial cancers. To this end, we have developed new small molecule
inhibitors and mouse models of EBV epithelial cancers to better understand these mechanisms and test
therapeutic strategies. The overarching hypothesis of Project 1 is that EBV epithelial malignancies
depend on the establishment of a distinct epigenetic state involving CpG methylator phenotype (CIMP)
and that key regulators of this epigenetic state are therapeutic targets in EBV epithelial carcinogenesis.

## Key facts

- **NIH application ID:** 10840306
- **Project number:** 5P01CA269043-02
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** PAUL M. LIEBERMAN
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $433,626
- **Award type:** 5
- **Project period:** 2023-05-11 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840306

## Citation

> US National Institutes of Health, RePORTER application 10840306, Epigenomic Drivers of EBV Epithelial Cancers (5P01CA269043-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10840306. Licensed CC0.

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