# Targeting non-canonical p16 signaling to improve radiation response and outcome in head and neck cancer

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $572,025

## Abstract

PROJECT SUMMARY
Head and neck cancer (HNC) is devastating. Even in the setting of curable disease, 1 of every 2 patients
diagnosed ultimately succumb. Additionally, survivors are left with debilitating toxicity due in large part to the
toxicity of radiation, leading to poor quality of life increased rates of depression and suicide. Therefore, there is
a critical need to develop precision oncology approaches which match radiation treatment approaches to HNC
biology.
HPV-associated (HPV+) HNC most commonly arises in the oropharynx (OPC) and is associated with much
greater sensitivity to radiation. However, up to 20% of patients with HPV+ tumors will also be failed by
radiation. Conversely, HPV- HNC that express p16 exhibit favorable outcomes compared to truly p16 negative
tumors. This proposal seeks to understand why this is so. Specifically, we have identified the protein p16, a
clinical surrogate for HPV, to be driving response to radiation and PARP inhibition outside of its usual cell cycle
regulatory function, by inhibiting DNA damage repair (DDR).
Although p16 is generally thought to be functionally inactive in HPV+ HNC, and absent in HPV- HNC, our data
suggests that p16 is functioning via non-canonical signaling in HNC to induce a state of BRCAness and is key
to understanding the differential radiation response in HPV+ and HPV- tumors. In this proposal we build upon
the substantial data we have generated for a non-canonical p16-mediated pathway active in HNC – leading to
upregulation of HUWE1, downregulation of USP7 and a shift in DDR – by first characterizing the relationship
between p16 and Sp1. Although, we have linked Sp1 to the activation of our non-canonical p16 signaling
pathway, as well as outcome in HNC following the combination of cisplatin and radiation, the nature of this
interaction is unclear. We will both characterize this interaction as well as utilize state-of-the-art methodology to
globally characterize the effects of p16 and Sp1 on mRNA and protein levels within HNC pre-clinical models
and patient tumors. We will then comprehensively examine the relationship between p16 and Sp1 on DDR and
radiation or Olaparib response using a combination of immunodeficient and -competent murine orthotopic
models as well as 400 HPV+ and HPV- OPC tumors treated uniformly with cisplatin and radiation in the largest
cohort of its kind to date. Finally, we will utilize USP7 inhibitors in clinical development in combination with
either radiation or PARP inhibition in pre-clinical models.
Completion of this project will establish biomarkers of outcome in both HPV+ and HPV- HNSCC downstream
of p16, evaluate USP7 as a viable target for sensitization to radiation and Olaparib, and identify novel targets
for precision medicine in HNC.

## Key facts

- **NIH application ID:** 10868518
- **Project number:** 5R01DE032337-02
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Heath Devin Skinner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $572,025
- **Award type:** 5
- **Project period:** 2023-06-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10868518

## Citation

> US National Institutes of Health, RePORTER application 10868518, Targeting non-canonical p16 signaling to improve radiation response and outcome in head and neck cancer (5R01DE032337-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10868518. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*