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） 口腔化或口干是头颈癌中最常见的放疗（RT）的并发症 （HNC）。它会对患者的生活质量产生不利影响，并使他们处于严重的晚期病情的危险中。当前的 减轻减发消息的策略是昂贵且无效的。强度调制放疗（IMRT）， 旨在避免一个腮腺，从而提高了刺激性唾液功能，但不能避免 下颌腺，由于其位置，这对于全天静止的唾液功能至关重要 与排水淋巴结相邻。我们和其他人发现唾液干/祖细胞（SSPC） 存在于成年腺中，并将这些细胞中的200个细胞注射到辐照的鼠下颌腺（SMG）中 可以恢复唾液功能。我们还发现，在SSPC中更新了AldH3A1的表达式，并且 在RT之前，之中和之后，用小分子激活剂对这种酶的激活导致了这种酶 RT后，SSPC产量增加和唾液功能保留。机械激活 RT后ALDH3A1增强了醛的清除，导致SSPC凋亡较少，导致功能性 保存。 Alhd3A1激活剂的使用不能保护HNC免受Xenographic模型中的辐射细胞杀伤。 这种酶的高表达并不影响接受化学放疗治疗的患者的预后。我们 已经从植物提取物中进行了屏幕，并确定了天然产物D-二烯烯，这证明了 成为ALDH3A1的高度选择性激活因子。在RT之前，之中和之后，口服D-二烯烯 导致RT后小鼠的唾液功能制备，但不能保护HNC细胞免受RT细胞杀伤的侵害。最多 重要的是，D-二烯烯已被研究为化学预防剂和癌症的抗癌疗法 患者，发现耐受性良好。由于其有利的安全性，D二烯烯是一个有前途的临床 临床翻译候选人。 基于这些数据，该提案的主要目标是：（1）确定最大耐受性 在I期剂量升级试验中接受HNC化学放疗的患者的D-二烯剂量 获取有关药物对唾液产生和患者生活质量的影响的初步数据，（2）确定 在没有RT的情况下激活AldH3A1的机制会导致SSPC自我更新增加，（3）至 评估D-二烯烯和/或C5AR1抑制对其他上皮组织的辐射保护的影响 皮肤，口服粘膜和食管粘膜。我们的最终目标是测试ALDH3A1是否激活 D-二烯可以减轻HNC患者RT诱导的静脉疾病，并开发出新的方法 保护正常组织免受头部和颈部和胸腔照射。