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

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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.