# Targeting replication stress and homologous recombination repair mechanisms in HPV-positive and negative head and neck cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $398,345

## Abstract

Abstract
Head and Neck squamous cell carcinoma (HNSCC) is the seventh most common cancer world-wide and
afflicts more than 50,000 individuals in the U.S. each year. Because of its anatomic location and poor survival
rate HNSCC is a devastating disease. Treatment can lead to profound functional defects and disfigurement. In
the U.S., HNSCC incidence is increasing in large part due to the human papillomavirus (HPV). Although HPV-
driven HNSCC generally has a better outcome than its HPV-negative counterpart, smokers with HPV-driven
HNSCC demonstrate inferior oncologic outcomes and are clinically defined as intermediate risk disease. The
significant complexity of HNSCC biology results in a complex clinical scenario, in which some patients are
overtreated while others are undertreated, leading to unnecessary long-term side effects and suboptimal
clinical response.
In the laboratory, we discovered that HPV+ HNSCCs have unusually high expression of genes involved in
DNA damage and repair (DDR) and are highly sensitive to drugs targeting RAD51, a DDR protein functioning
in homologous recombination repair (HRR) that also protects cells from replication stress (RS). We
hypothesize that the HPV-driven biology of this genomic subset of HNSCC renders them more sensitive to
drugs targeting RS and HRR. We further hypothesize that HPV-neg HNSCC that share the same pattern of
overexpressed DDR genes may also be susceptible to drugs targeting RS/HRR. In this translational proposal,
we plan to: 1) Determine the efficacy and feasibility of replacing cisplatin with a RAD51 inhibitor to sensitize
tumors to radiation using preclinical models of HPV+ HNSCC; 2) Elucidate the molecular mechanisms
governing sensitivity of HPV+HNSCC to RAD51 inhibition; 3) Determine if drug combinations targeting RS or
HRR are efficacious in preclinical models of HNSCC. Progress in this area could lead directly to human clinical
trials that may improve tumor control with less toxicity.

## Key facts

- **NIH application ID:** 10297645
- **Project number:** 1R01DE030104-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** MITCHELL J. FREDERICK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $398,345
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10297645

## Citation

> US National Institutes of Health, RePORTER application 10297645, Targeting replication stress and homologous recombination repair mechanisms in HPV-positive and negative head and neck cancer (1R01DE030104-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10297645. Licensed CC0.

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