# Targeting IKKepsilon-mediated nucleotide synthesis in KSHV-associated lymphoma

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2024 · $379,725

## Abstract

Abstract
Title: Targeting IKKepsilon-mediated nucleotide synthesis in KSHV-associated lymphoma
Human gamma herpesviruses, including Kaposi's sarcoma-associated herpesvirus (KSHV) and
Epstein-Barr virus (EBV), are causative agents of diverse malignancies in immune-
compromised individual, including AIDS patients and organ transplant recipients. In addition to
KS, KSHV is invariably associated with two types of lymphoma, primary effusion lymphoma
(PEL) and multicentric Castleman's disease (MCD). No vaccine or effective treatment is
available for KSHV-associated malignancies, though antiviral therapy targeting viral thymidine
kinase is an option with limited efficacy.
We have an outstanding interest in virus-host interaction involving innate immune defense
system. Recently, we discovered that KSHV exploits the IKKepsilon kinase to reprogram
metabolism in KSHV latently-infected PEL cells. Specifically, KSHV activates IKKepsilon to fuel
de novo nucleotide synthesis via activating key metabolic enzymes known as glutamine
amidotransferases. In doing so, IKKepsilon promotes the proliferation of KSHV-infected PEL
cells and depletion of IKKepsilon arrests these cells at G0/G1 phase. This study will delineate
the molecular interaction that KSHV activates IKKepsilon in metabolic reprogramming to support
immortal proliferation of PEL cells. We have developed novel small-molecule inhibitors of
IKKepsilon and glutamine amidotransferases. We will explore these drug-like molecules to
target IKKepsilon and glutamine amidotransferase to impede PEL cell proliferation. Our work
will not only elucidate fundamental mechanism governing PEL cell metabolism and proliferation,
but also provide proof-of-concept that targets host factors to treat KSHV-associated
malignancies.

## Key facts

- **NIH application ID:** 10879181
- **Project number:** 5R01CA285192-02
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Pinghui Feng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $379,725
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10879181

## Citation

> US National Institutes of Health, RePORTER application 10879181, Targeting IKKepsilon-mediated nucleotide synthesis in KSHV-associated lymphoma (5R01CA285192-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10879181. Licensed CC0.

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