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

• 批准号: 10707889
• 负责人: Quynh-Thu Xuan Le
• 金额: $ 39.26万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 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/10707889
• 关键词: Address; Adult; Aldehydes; Ames Assay; Apoptosis; Cancer Patient; Cells; Chemopreventive Agent; Chemotherapy and/or radiation; Chest; Clinic; Clinical Trials; Collaborations; Complication; Cytoprotection; Data; Deglutition; Dental caries; Dermatitis; Dose; Eating; Enzyme Activation; Enzymes; Epithelium; 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; 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; Radiosensitization; Reactive Oxygen Species; Recurrence; 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; 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; radioprotected; safety testing; saliva function; side effect; small molecule; stem cell self renewal; stem cell survival; stem cells; treatment duration; tumor growth

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) 呼吸功能减退或口干是头颈癌放射治疗最常见的并发症。 (HNC)。它对患者的生活质量产生不利影响，并使他们面临严重晚期疾病的风险。当前 缓解肥胖症的策略既昂贵又无效。调强放射治疗(IMRT) 旨在节省一个腮腺，导致了刺激唾液功能的改善，但它不能幸免 颌下腺，因为它们的位置，对一天中休息的唾液功能至关重要 与引流的淋巴结相邻。我们和其他人发现唾液干细胞/祖细胞(SSPC) 并将其中约200个细胞注射到照射后的小鼠下颌下腺(SMG)中 可以恢复唾液功能。我们还发现ALDH3A1在SSPC中表达上调，并且 在RT之前、期间和之后用小分子激活剂激活该酶导致 RT后SSPC产量增加，唾液功能保留。机械地激活 ALDH3A1增强RT后乙醛的清除，导致SSPC凋亡减少，导致功能性 保护。在异种移植模型中，ALHD3A1激活剂的使用不能保护HNC免受辐射细胞的杀伤 该酶的高表达并不影响放化疗患者的预后。我们 从植物提取物中筛选出一种天然产物d-柠檬烯，这证明了 作为ALDH3A1的高度选择性激活剂。放射治疗前、中、后口服d-柠檬烯 结果在RT后保留了小鼠的唾液功能，但不能保护HNC细胞免受RT细胞的杀伤。多数 重要的是，d-柠檬烯已被用作癌症的化学预防药物和抗癌治疗药物。 患者，并被发现耐受性良好。由于其良好的安全性，d-柠檬烯是一种很有前途的临床药物。 临床翻译候选人。 基于这些来自的数据，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化疗的患者中d-柠檬烯的剂量 获取有关该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 皮肤、口腔粘膜和食道粘膜。我们的最终目标是测试ALDH3A1是否通过 D-柠檬烯可以减轻HNC患者放疗引起的口干症，并开发新的治疗方法 保护正常组织免受头颈部和胸部的辐射。