# Dissecting NF-kB pathway in HPV-associated head and neck cancer

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2024 · $536,605

## Abstract

Project summary
 The incidence of HPV-associated (HPV+) head and neck squamous cell carcinoma (HNSCC) has
dramatically increased over the last few decades and continues to rise. Despite the magnitude of this epidemic,
mechanisms of HPV-driven carcinogenesis in HPV+ HNSCC have not been thoroughly investigated. Compared
to patients with tobacco-associated HNSCC, those with HPV+ HNSCC have increased overall survival and
higher response to treatment, which usually consists of chemo- and radiation therapy; however, survivors
frequently suffer from treatment’s toxic side effects, such as swallowing and speech dysfunction. In addition,
approximately 25% of HPV+ HNSCC patients develop recurrent or metastatic disease, for which there are limited
treatment options. A pressing goal in head and neck oncology is to decrease the morbidity of therapy for HPV+
HNSCC through treatment de-escalation. However, biomarkers that identify HPV+ patients with good prognosis,
who may be appropriate for de-escalation therapy, are lacking. Using three independent cohorts, we found that
constitutively active NF-κB (usually arising from genetic defects in NF-κB regulators, including TRAF3 and CYLD)
correlates with survival and should be explored as a prognostic biomarker in HPV+ HNSCC. Our preliminary
data suggest that survival benefits of patients, whose tumors harbor overactive NF-κB, are attributed to better
tumor response to therapy and that both, inherent NF-κB-driven tumor characteristics (e.g. downregulated
expression of oxidative stress response, NRF2 target genes), as well as a distinct tumor microenvironment (e.g.
elevated number of tumor infiltrating CD4+ T cells), may contribute to increased sensitivity of NF-κB active
tumors to radiation. We previously reported that mutations in TRAF3 and CYLD were associated with a lack of
HPV integration, leading us to hypothesize that NF-κB activation may enable cells to maintain HPV episomes.
Since the canonical HPV carcinogenesis model depends on HPV integration, we also hypothesize that activation
of NF-κB may be critical for an alternative mechanism of HPV carcinogenesis driven by HPV episomal
maintenance. To explore our hypothesis, in Specific Aim 1, we will investigate the impact of NF-κB signaling on
HPV gene expression and episomal maintenance. In Specific Aim 2, we will explore the significance of NF-κB
pathway on cellular proliferation, survival, and cellular transformation in response to HPV. Finally, Specific Aim
3 will explore mechanisms of NF-κB mediated radiation sensitivity in HPV+ HNSCC.

## Key facts

- **NIH application ID:** 10796961
- **Project number:** 5R01DE031297-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Natalia Issaeva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $536,605
- **Award type:** 5
- **Project period:** 2023-03-01 → 2027-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10796961

## Citation

> US National Institutes of Health, RePORTER application 10796961, Dissecting NF-kB pathway in HPV-associated head and neck cancer (5R01DE031297-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10796961. Licensed CC0.

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