# The P2X7 receptor for ATP as a therapeutic target in the prevention of radiation-induced salivary gland dysfunction

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2024 · $506,444

## Abstract

Summary
Despite technological advancements in head and neck squamous cell carcinoma (HNSCC) radiotherapies,
collateral damage to surrounding normal tissues such as salivary glands following ionizing radiation (IR) remains
a significant problem for these patients and severely diminishes their quality of life. It is estimated that >95% of
HNSCC patients exhibit xerostomia and salivary gland hypofunction following the irradiation regimen and >73%
of these patients continue to suffer for months to years after completion of radiotherapy. The lack of treatment
options to prevent IR-induced xerostomia or recover salivary function is compounded by a limited understanding
of the underlying mechanisms that mediate chronic IR-induced salivary dysfunction. Our previous studies
demonstrate the action of extracellular ATP (eATP), a key “alarmin” molecule in damaged tissue that contributes
to IR-induced salivary dysfunction, can be inhibited by pharmacological or genetic blockade of P2X7Rs for eATP,
thereby conferring significant radioprotection to salivary glands. In addition, our studies show that radioprotection
from P2X7R antagonism maintains normal salivary output through day 30 post-IR, although longer time periods
relevant to the treatment of IR-induced chronic xerostomia and salivary dysfunction have not been investigated.
Our ultimate goal is to use P2X7R antagonists as radioprotective agents to retain salivary gland function in head
and neck cancer patients undergoing radiotherapy, although there is little information available on whether
P2X7R antagonists will interfere with tumor regression achieved by radiotherapy, and proposed studies will
address this gap in knowledge. The overall goal of this proposal is to develop an approach using P2X7R
antagonism to prevent IR-induced salivary dysfunction in head and neck cancer patients receiving radiotherapy
without inhibiting the IR-induced regression of HNSCC tumors. Successful completion of this proposal will greatly
accelerate translation of this novel pharmacological approach to human patients undergoing IR therapies for
head and neck cancer. The following specific aims will be pursued:
Specific Aim 1 will develop a radioprotective approach using P2X7R antagonism in an irradiated syngeneic
mouse model of HNSCC that preserves salivary gland function and anti-tumor responses.
Specific Aim 2 will investigate the durability of the radioprotective effects of P2X7R antagonism towards
developing an approach for chronic salivary dysfunction that occurs in HNSCC patients following radiotherapy.
Specific Aim 3 will evaluate the contribution of eATP release and purinomic signaling downstream of P2X7R
activation to IR-induced salivary gland dysfunction in mouse and human salivary gland organotypic cultures
towards identifying alternative radioprotective targets and translating findings in mice to humans.

## Key facts

- **NIH application ID:** 10804660
- **Project number:** 5R01DE032032-02
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** GARY Andrew WEISMAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $506,444
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10804660

## Citation

> US National Institutes of Health, RePORTER application 10804660, The P2X7 receptor for ATP as a therapeutic target in the prevention of radiation-induced salivary gland dysfunction (5R01DE032032-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10804660. Licensed CC0.

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