# Project 2: ALDH3A1 Activation for Radioprotection of Salivary Glands and Other Head and Neck Epithelial Tissues

> **NIH NIH P01** · STANFORD UNIVERSITY · 2023 · $392,627

## Abstract

Project Abstract (Project 2)
Hyposalivation or dry mouth is the most common complication of radiotherapy (RT) in head and neck cancer
(HNC). It adversely impacts patients’ quality of life and places them at risk for significant late morbidities. Current
strategies to mitigate hyposalivation are costly and ineffective. Intensity modulated radiotherapy (IMRT), which
aims to spare one parotid gland, has resulted in improved stimulatory salivary function, but it cannot spare the
submandibular glands, which are crucial for resting salivary function throughout the day, because of their location
adjacent to the draining lymph nodes. We and others have found that salivary stem/progenitor cells (SSPCs)
exist in adult glands and that injection of ~200 of these cells into irradiated murine submandibular glands (SMG)
could restore saliva function. We have also found that ALDH3A1 expression is upregulated in SSPCs, and
that activation of this enzyme with a small molecular activator before, during and after RT resulted
increased SSPC yield and preservation of saliva function after RT. Mechanistically activation of
ALDH3A1 enhanced clearance of aldehyde after RT, leading less SSPC apoptosis, resulting in functional
preservation. The use of ALHD3A1 activator did not protect HNC from radiation cell kill in a xenograft model
and high expression of this enzyme did not affect the prognosis of patients treated with chemoradiation. We
have performed a screen from plant extracts and identified a natural product, d-limonene, which proves
to be a highly selective activator of ALDH3A1. Oral administration of d-limonene before, during and after RT
resulted in preservation of saliva function in mice after RT, but did not protect HNC cells from RT cell kill. Most
importantly, d-limonene has been studied as a chemoprevention agent and an anti-cancer therapy in cancer
patients and found to be well tolerated. Because of its favorable safety profile, d-limonene is a promising clinical
candidate for clinical translation.
Based on these data from, the main objectives of this proposal are: (1) To determine the maximum tolerated
dose of d-limonene in patients undergoing chemoradiation for HNC in a phase I dose escalation trial and to
obtain preliminary data on the effect of the drug on saliva production and patient quality of life, (2) To identify the
mechanism by which activation of ALDH3A1 in the absence of RT leads to increased SSPC self-renewal, (3) To
assess the effect of d-limonene and/or C5aR1 inhibition on radioprotection of other epithelial tissues including
skin, oral mucosa and esophageal mucosa. Our ultimate goals are to test whether ALDH3A1 activation with
d-limonene can mitigate RT-induced xerostomia in HNC patients and to develop novel approaches to
protect normal tissues from head and neck and thoracic irradiation.

## Key facts

- **NIH application ID:** 10707889
- **Project number:** 5P01CA257907-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Quynh-Thu Xuan Le
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $392,627
- **Award type:** 5
- **Project period:** 2022-09-21 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10707889

## Citation

> US National Institutes of Health, RePORTER application 10707889, Project 2: ALDH3A1 Activation for Radioprotection of Salivary Glands and Other Head and Neck Epithelial Tissues (5P01CA257907-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10707889. Licensed CC0.

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