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

项目2：ALDH3A1激活对唾液腺和其他头颈上皮组织的辐射防护

基本信息

批准号：
10334200
负责人：
Quynh-Thu Xuan Le
金额：
$ 41.36万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-21 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10334200
关键词：
Address Adult Aldehydes Ames Assay Apoptosis Cancer Patient Cells Chemopreventive Agent Chemotherapy and/or radiation Chest Clinic Clinical Trials Collaborations Complication Data Deglutition Dental caries Dermatitis Dose Eating Enzyme Activation Enzymes Epithelial Esophageal mucous membrane Esophagitis European Organization for Research and Treatment of Cancer Functional disorder Genes Genetic Gland Glutaminase Goals Head and Neck Cancer Head and neck structure In Vitro Injections Intensity-Modulated Radiotherapy Intestinal Mucosa Knowledge Lead Location Mass Fragmentography Maximum Tolerated Dose Measures Mitochondria Molecular Morbidity - disease rate Morphology Mucositis Mus Natural Products Normal tissue morphology Oral Oral Administration Oral mucous membrane structure Outcome Parotid Gland Pathway interactions Patient Outcomes Assessments Patients Pharmaceutical Preparations Phase Plant Extracts Plasma Platinum Procedures Production Quality of life Questionnaires Radiation Radiation Injuries Radiation Protection Radiation Tolerance Radiation induced damage Radiation therapy Reactive Oxygen Species Rest Risk Safety Saliva Salivary Salivary Glands Skin Statistical Data Interpretation Submandibular gland Survivors Terpenes Testing Therapeutic Index Time Tissues Toxic effect Work Xenograft Model Xenograft procedure Xerostomia aldehyde dehydrogenases base bone cancer cell cancer radiation therapy cancer therapy carcinogenicity cell killing chemoradiation clinical candidate clinical translation comparison group cost draining lymph node follow-up head and neck cancer patient implantation improved in vivo instrument irradiation limonene mouse model mutant novel novel strategies oral infection patient prognosis phase I trial preservation primary endpoint safety testing saliva function self-renewal side effect small molecule stem stem cell survival stem cells treatment duration tumor growth

项目摘要

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.

项目摘要（项目2）唾液分泌不足或口干是头颈癌放疗 (RT) 最常见的并发症 (HNC)。它对患者的生活质量产生不利影响，并使他们面临严重的晚期发病风险。缓解唾液分泌不足的策略成本高昂且无效。旨在保留一个腮腺，改善了刺激性唾液功能，但不能保留颌下腺，由于其位置，对于全天的休息唾液功能至关重要我们和其他人发现唾液干/祖细胞（SSPC）位于引流淋巴结附近。存在于成人腺体中，将约 200 个这些细胞注射到受辐射的小鼠颌下腺 (SMG) 中我们还发现 SSPC 中 ALDH3A1 的表达上调，并且在 RT 之前、期间和之后用小分子激活剂激活该酶会导致 RT 机械激活后 SSPC 产量增加并保留唾液功能。 ALDH3A1 增强 RT 后乙醛的清除，导致 SSPC 细胞凋亡减少，从而导致功能性在异种移植模型中，使用 ALHD3A1 激活剂并不能保护 HNC 免受辐射细胞杀死。并且该酶的高表达并不影响接受放化疗的患者的预后。对植物提取物进行了筛选并鉴定出一种天然产物 d-柠檬烯，这证明是 ALDH3A1 的高度选择性激活剂，在 RT 之前、期间和之后口服 d-柠檬烯。导致 RT 后小鼠唾液功能的保留，但不能保护 HNC 细胞免受 RT 细胞杀死。重要的是，d-柠檬烯已被研究作为癌症的化学预防剂和抗癌疗法由于其良好的安全性，d-柠檬烯是一种有前景的临床药物。临床翻译候选人。根据这些数据，本提案的主要目标是： (1) 确定最大容忍度在 I 期剂量递增试验中，接受 HNC 放化疗的患者使用 d-柠檬烯的剂量获得有关药物对唾液产生和患者生活质量影响的初步数据，（2）确定在没有 RT 的情况下激活 ALDH3A1 会导致 SSPC 自我更新增加的机制，(3) 评估 d-柠檬烯和/或 C5aR1 抑制对其他上皮组织辐射防护的影响，包括我们的最终目标是测试皮肤、口腔粘膜和食道粘膜是否与ALDH3A1激活有关。 d-柠檬烯可以减轻 HNC 患者放疗引起的口干症，并开发新方法保护正常组织免受头颈部和胸部的照射。