# Synthetic Lethal Therapy for HPV-Negative Head and Neck Cancer

> **NIH NIH P50** · YALE UNIVERSITY · 2023 · $74,139

## Abstract

Project Abstract / Summary
Head and neck squamous cell carcinomas (HNSCC) affect more than 890,000 individuals annually worldwide,
and lead to over 450,000 deaths. Although significant progress has been made treating HNSCC including
immune checkpoint blockade (ICB), intrinsic and adaptive resistance present great challenges to improving
patient outcomes. In these cancers, the most dominant genetic alteration is mutation of the tumor suppressor
TP53, which accounts for over 85% of patients. The Yale Head and Neck SPORE seeks to address critical
barriers to cure of HNSCC due to resistance to immune, DNA damaging and targeted therapy. Our previous
work identified synthetic lethality of inhibition of Aurora Kinase A (AURKA) and WEE1, a G2/M checkpoint kinase,
leading to induction of cell death for HNSCC cell lines in vitro and xenografts and patient-derived xenografts in
vivo. These innovative combinations of kinase inhibitors represent a completely new approach to treating TP53-
mutated cancer. This study will help us to combination therapies to the clinic of HPV-negative HNSCC,
particularly in the context of synthetic lethality and TP53mut-mediated drug response targeting cell cycle
regulators. The proposed work will determine how different TP53 mutations affect drug response to AURKA
inhibitor in combination with WEE1 inhibitor in HNSCC. Aim 1 will explore the relationship between TP53
mutation genotype and drug response to AURKA and WEE1 inhibitors in HPV-negative HNSCC cells. We will
perform treatment combinations on isogenic cell lines with different TP53 genotypes including mutations strongly
disruptive, weakly disruption, gain of function, loss of function and wild type. Aim 2 will preclinically assess the
efficacy of the combinational treatment to generate response biomarkers and model potential trial design by
using a new genetically engineered mouse model of HNSCC driven both by Tp53 and Cdkn2a mutations. This
Diversity Supplement will provide Mr. Barrantes with an opportunity to learn and develop technical,
communicative, and critical thinking research skills in the realm of cancer therapeutics. This supplement will also
support additional pre-requisite coursework, and the opportunity for him to demonstrate his ability to complete
graduate level coursework in the Yale Cancer Biology T32 Introduction to Cancer Biology Course. We expect
his research success to include at least one scientific publication resulting from this project. Altogether, we
anticipate that this research experience will provide Mr. Barrantes with opportunities for development as a
productive researcher and more competitive application for medical or graduate school.

## Key facts

- **NIH application ID:** 10838999
- **Project number:** 3P50DE030707-04S2
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** BARBARA BURTNESS
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $74,139
- **Award type:** 3
- **Project period:** 2020-09-22 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10838999

## Citation

> US National Institutes of Health, RePORTER application 10838999, Synthetic Lethal Therapy for HPV-Negative Head and Neck Cancer (3P50DE030707-04S2). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10838999. Licensed CC0.

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