# Synthetic Lethal Targeting of CREBBP/EP300 in Head and Neck Squamous Cell Carcinoma

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $563,756

## Abstract

Head and neck squamous cell carcinomas (HNSCC) are a diverse group of tumors from the upper
aerodigestive tract with relatively poor outcomes and limited targeted therapeutic options. Most patients are
treated with a combination of DNA damaging agents (platinum, XRT). Recent genomic characterization of
these tumors has not identified targetable oncogenic drivers, thus emphasizing the need to develop rational
genomic-based approaches to increase sensitivity to treatments that induce DNA damage. We performed an in
vivo functional genomic screen in genomically characterized HNSCC cell lines alone or in combination with
DNA damaging agents. Knock-down of CREBBP or EP300 was identified as a potential mechanism to
sensitize cells to the DNA damage response. CREBBP and EP300 are homologous multifunctional
bromodomain-containing acetyltransferases that can regulate many proteins and pathways. Importantly,
CREBBP and EP300 are mutated in 13% of HNSCC and sensitivity seems to be associated with those
alterations, suggesting a synthetic cytotoxicity relationship. Additionally, these genes are druggable and small
molecule inhibition of CREBBP increases DNA damage induction and persistence in response to radiation
treatment and increased apoptotic cell death. We hypothesize that the CREBBP/EP300 pathway is both a
biomarker and a therapeutically relevant target to sensitize HNSCC to currently used DNA damaging
treatments. We propose to examine the genomic basis for this synthetic cytotoxicity and understand how
mutations modulate the phenotype. We will also identify global changes to histone acetylation caused by
modulation of CREBBP or EP300 and aim to understand how those changes impact the response to DNA
damage. Additionally, therapeutic agents that modulate these genes will be tested for their efficacy in
preclinical models with the goal of generating sufficient data to justify a clinical trial. Finally, we will perform
another in vivo screen to identify other targets that can sensitize to inhibition of CREBBP with reduced toxicity.
Overall, this project will examine an exciting new therapeutic target and candidate biomarker for a tumor type
that is driven by loss of tumor suppressor genes and has proven difficult to target.

## Key facts

- **NIH application ID:** 9913499
- **Project number:** 5R01DE028061-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Curtis Pickering
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $563,756
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913499

## Citation

> US National Institutes of Health, RePORTER application 9913499, Synthetic Lethal Targeting of CREBBP/EP300 in Head and Neck Squamous Cell Carcinoma (5R01DE028061-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9913499. Licensed CC0.

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