# Methionine and PI3K Metabolism Drive CIMP in EBV Epithelial Cancers

> **NIH NIH P01** · WISTAR INSTITUTE · 2024 · $444,045

## Abstract

PROJECT 3 – PROJECT SUMMARY
Epstein-Barr virus (EBV) is associated with multiple epithelial cell diseases, including gastric cancer and
nasopharyngeal carcinoma. Despite its B-cell tropism, more than half of the 200,000 EBV-associated cancers
that occur annually are gastric and nasopharyngeal carcinomas. The Cancer Genome Atlas project identified
EBV-infected gastric cancer as one of the four biologically distinct subtypes. Extreme tumor genome CpG island
methylator phenotype (CIMP) and gain-of-function PI3K mutations are salient features, suggesting
interconnected driver roles in EBV+ GC. In fact, EBV+ gastric cancer has the highest level of DNA methylation
of any human cancer. Hypermethylation and elevated PI3K activity are also characteristic of EBV+ NPC and
Burkitt lymphoma, further suggesting a close pathogenetic relationship of these oncogenic properties with highly
restricted forms of EBV latency. Yet, much remains to be learned about how latent EBV mutation together with
tumor driver mutations result in epithelial cancers, and how these can be targeted by precision approaches. We
therefore used EBV+ epithelial tumor cell RNAseq and CRISPR/Cas9 screens to identify host factors whose
knockout is synthetic lethal with reversal of CIMP by the hypomethylating agent decitabine or upon blockade of
PI3K hyperactivity by the highly selective antagonist alpelisib. Our central hypothesis is that EBV+ epithelial
cancers rely on cross-talk between latent viral genomes, and hyperactive PI3K and CIMP, disruption of
which can be targeted in synthetic lethal approaches. Our Aims are to (1) Define the role of latent EBV in
driving CIMP; (2) Define the role of hyperactive PI3K signaling in EBV+ epithelial cancers in support of CIMP;
(3) Define key synthetic lethal vulnerabilities upon EBV+ epithelial cancer CIMP reversal. Collectively, these
studies are expected to identify how EBV-infected epithelial cancers subvert host methionine and PI3K
metabolism pathways to support CIMP, and how in turn CIMP not only silences tumor suppressors, but also
plays key roles in guarding against DNA damage. Our studies may therefore support strategies to develop
rational therapeutic approaches for EBV-associated epithelial cancers.

## Key facts

- **NIH application ID:** 10840318
- **Project number:** 5P01CA269043-02
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Benjamin Elison Gewurz
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $444,045
- **Award type:** 5
- **Project period:** 2023-05-11 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840318

## Citation

> US National Institutes of Health, RePORTER application 10840318, Methionine and PI3K Metabolism Drive CIMP in EBV Epithelial Cancers (5P01CA269043-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10840318. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*