# Dual p300 and p53 reactivation in HPV+ head and neck cancer

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $575,570

## Abstract

Project Summary
Incidence of HPV+ OPC has been increasing for several decades and this upward trend is expected to continue
until at least 2060. Current first-line modalities to manage HPV+ OPC patients are effective but not without
limitations. A key event in HPV-driven tumorigenesis is the inactivation of the p53 tumor suppressor program.
HPV oncogene, E6, inactivates p53 through two distinct pathways: HPVE6 promotes the assembly of the
HPVE6-E6AP-p53 trimeric protein complex resulting in ubiquitination and degradation of p53, and HPVE6
directly binds to p300 to block p300-directed acetylation and activation of p53. We hypothesized that disrupting
the HPVE6-p300 interaction will liberate sufficient p300 to restore p53 and p300 functionality simultaneously in
HPV+ OPC. Our team initiated a drug discovery platform to target the HPVE6-p300 interaction. Our work showed
that in HPV+ OPC models: (a) HPVE6 binds to the CH1 domain of p300, (b) our lead molecule, OHM1, a
CH1/p300 ligand, disrupts HPVE6-p300 interaction and reactivates p53 and p300, (c) OHM1 is active in vitro
and in vivo, and (d) concurrent OHM1+cisplatin combination treatment yields durable complete anti-tumor
responses in vivo. Our results are very compelling and, supports further research and development of dual p53
and p300 reactivation as a therapeutic strategy for HPV+ OPC. In this project, we propose to extensively
determine the mechanisms of action of p53 and p300 reactivation in response to OHM1 in HPV+ OPC. The
specific aims are: (1) determine if OHM1 modulates the p53 post-translational modification code to control p53
functionality and levels, and promote anti-cancer activity in HPV+ OPC, (2) to determine if OHM1 reshapes the
tumor-microenvironment and boost immunotherapy response in HPV+ OPC.

## Key facts

- **NIH application ID:** 10999618
- **Project number:** 1R01DE034300-01
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** QUINTIN PAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $575,570
- **Award type:** 1
- **Project period:** 2024-07-15 → 2029-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10999618

## Citation

> US National Institutes of Health, RePORTER application 10999618, Dual p300 and p53 reactivation in HPV+ head and neck cancer (1R01DE034300-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10999618. Licensed CC0.

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