# Targeting the DNA Damage Response in HPV+ Head and Neck Cancer

> **NIH NIH K99** · UNIVERSITY OF PENNSYLVANIA · 2022 · $6,253

## Abstract

Project Summary
Human papilloma virus (HPV)-positive head and neck squamous cell carcinoma (HNSCC) is a growing public
health burden and has already surpassed cervical cancer as the most common HPV-related malignancy in the
United States. While HPV+ HNSCC patients have generally good survival, they suffer from life-long
chemoradiotherapy-related morbidities. Current data is insufficient to inform de-intensification of standard
chemoradiotherapy or the development of targeted therapies. My ultimate goal is to understand the
mechanisms by which HPV disrupts DNA damage response (DDR) signaling during HNSCC development,
and to thereby inform the rational design of new targeted therapies. In considering new strategies to effectively
control HPV+ HNSCC, I noted that HPV's oncogenic E6 and E7 proteins abrogate tumor suppressor pathways
and impair DDR signaling to cause genomic instability. The Mendez lab and others have established DDR
kinase WEE1 inhibition via the specific inhibitor AZD1775 (WEE1i) as a new therapeutic strategy in HNSCC,
and that HPV+ HNSCC tumors are hypersensitive. WEE1 inhibition causes S-phase replication stress (RS)
and irreparable DNA damage. Combined with genotoxic chemotherapy (e.g., cisplatin), WEE1i abrogates the
G2/M checkpoint and causes premature mitosis. I recently showed that HPV16 E6/E7 oncoproteins sensitize
HNSCC cells to WEE1i monotherapy through activation of a FOXM1-CDK1 circuit that drives mitotic gene
expression and DNA damage. I also showed that elevated basal FOXM1 activity predisposes HPV+ HNSCC to
WEE1i-induced toxicity. Next, I used an RNAi genetic screen to identify RS and DDR targets that synergize
with WEE1i; based on my findings to date, I hypothesize that disruption of RS and DDR pathways by E6/E7
provide exploitable vulnerabilities for a combination targeted therapy that also includes WEE1i. I plan to clarify
the mechanisms by which HPV sensitizes cancer cells to WEE1i-induced replication failure (Aim 1) and
compromises DNA repair pathways upon WEE1 inhibition (Aim 2). I will use murine cancer models to test
novel therapeutic combinations for targeting RS/DDR defects in HPV+ HNSCC and identify the situations in
which they are most effective. In parallel, I will use a targeted quantitative proteomics approach to determine
the E6/E7-specific RS and DDR responses to WEE1i, and multi-panel flow cytometry to determine the
WEE1iassociated changes in the immune landscape of E6/E7-driven tumors in immunocompetent mice. This
award will help me develop my scientific ideas and increase my competency in working with the mouse models
that faithfully recapitulate human cancer. The scientific advances that I make during this training period will be
critical to my ultimate goal of establishing an independent research program that focuses on how HPV drives
HNSCC development and how HPV+ HNSCC might be more safely and effectively treated.

## Key facts

- **NIH application ID:** 10915126
- **Project number:** 7K99DE030194-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Ahmed Mohamed Diab
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $6,253
- **Award type:** 7
- **Project period:** 2023-09-01 → 2024-06-16

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915126

## Citation

> US National Institutes of Health, RePORTER application 10915126, Targeting the DNA Damage Response in HPV+ Head and Neck Cancer (7K99DE030194-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10915126. Licensed CC0.

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