Radioprotective effect of p53 against oral mucositis

p53对口腔粘膜炎的放射防护作用

• 批准号: 10775974
• 负责人: Chang-Lung Lee
• 金额: $ 50.68万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-07 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10775974
• 关键词: Acceleration; Acute; Affect; Alleles; Blood capillaries; Body Weight; Body Weight decreased; C57BL/6 Mouse; Cell Cycle Arrest; Cell Death; Cell Lineage; Cell Proliferation; Cell Survival; Cells; DNA Damage; DNA Markers; Data; Defect; Dilatation - action; Dose Limiting; Epithelial Cells; Epithelium; Exhibits; G2/M Checkpoint Pathway; GADD45A gene; Genetic Transcription; Genetically Engineered Mouse; Goals; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Histopathology; Human; Human Papillomavirus; Impairment; Incidence; Inflammation; Injury; Intake; Knockout Mice; Maintenance; Malignant Neoplasms; Mediating; Metabolic; Mitosis; Mitotic; Modeling; Mus; Mutate; Mutation; Myeloid Cells; Natural regeneration; Normal tissue morphology; Nutritional status; Oral; Oral mucous membrane structure; Patient-Focused Outcomes; Patients; Persons; Play; Radiation; Radiation Injuries; Radiation Protection; Radiation therapy; Recovery; Role; Signal Transduction; Somatic Cell; Stress; Superoxide Dismutase; TP53 gene; Testing; Therapeutic; Toxic effect; Transactivation; Transplantation; United States; Vascular Endothelial Cell; clinical development; experimental study; gain of function; genome integrity; in vivo; inhibitor; insight; irradiation; knock-down; loss of function; mimetics; mouse model; mutant; novel; novel therapeutic intervention; opioid use; oral cavity epithelium; oral mucositis; pharmacologic; prevent; radiation response; response; small hairpin RNA; small molecule; treatment response; tumor

ABSTRACT Head and neck squamous cell carcinoma (HNSCC) represents the sixth most common cancer worldwide. The Global Cancer Observatory predicts a 30% increase in annual incidence by 2030 with approximately 1.08 million new cases/year. Radiation therapy (RT) plays an integral role in treating HNSCC; however, head and neck RT is associated with significant toxicity in the oral mucosa. This toxicity, termed radiation-induced oral mucositis (RIOM), can lead to opioid use, reduced oral intake/poor nutritional status, and the need for treatment breaks, all of which are correlated with worse outcomes for patients with HNSCC. As current treatment options for RIOM are limited, there is an unmet need to develop novel radioprotectors that will widen the therapeutic window of head and neck RT. Our long-term goal aims to develop novel therapeutic strategies that will prevent or reduce RIOM without sacrificing tumor control. The overall objective of this application is to define the role of p53 in regulating RIOM. The p53 gene is mutated in >80% of human papillomavirus negative HNSCC, yet it remains wild type in adjacent normal tissues. The p53 protein plays a critical role in regulating various cellular responses to stress such as cell death, cell survival, metabolic adaptation, and maintenance of genomic integrity. In normal oral epithelium, RT markedly increases the level of p53 protein as well as its transcriptional target and negative regulator Mdm2. However, how p53 affects damage and recovery of the oral epithelium following irradiation remains poorly understood. Based on our preliminary data generated from p53 knockout mice, we hypothesize that the response of p53 to acute DNA damage plays a crucial role in promoting the regeneration of oral epithelium following severe radiation injury. Therefore, treatment with Mdm2 inhibitors that enhance p53-dependent signaling specifically in cells harboring a functional p53 protein before and during RT will ameliorate acute injury of p53 wild-type oral epithelium without decreasing the therapeutic response of p53 mutant HNSCC. We will test this hypothesis through both loss-of-function and gain-of-function approaches to modulate the response of p53 to radiation using genetically engineered mouse models and small molecule Mdm2 inhibitors. The impact of Mdm2 inhibition on RIOM will be evaluated in normal and tumor-bearing mice. Successful completion of the proposed study will provide mechanistic insights into the crucial role of p53 in promoting the regeneration of oral epithelium following acute radiation injury. Our findings will provide a proof-of-concept to support clinical development of Mdm2 inhibitors as radioprotectors for RIOM to widen the therapeutic window of RT for treating p53 mutant HNSCC.

抽象的 头颈部鳞状细胞癌（HNSCC）代表了第六个最常见的癌症 全世界。全球癌症天文台预测，到2030年，每年发病率将增加30％ 大约108万个新案例/年。放射疗法（RT）在治疗HNSCC中起着不可或缺的作用。 但是，头颈RT与口腔粘膜的显着毒性有关。这种毒性称为 辐射诱导的口服粘膜炎（RIOM）可导致阿片类药物使用，口服摄入/营养状况降低以及 治疗休息的需求与HNSCC患者的预后较差有关。作为 RIOM的当前治疗选择是有限的，有未满足的需要开发新型的放射线保护剂 将扩大头颈部RT的治疗窗口。我们的长期目标旨在发展新颖的治疗性 不牺牲肿瘤控制的而预防或减少RIOM的策略。总体目标 应用是定义p53在调节RIOM中的作用。 p53基因在> 80％的人类中被突变 乳头瘤病毒负HNSCC，但在相邻的正常组织中仍然是野生类型。 p53蛋白玩具 在调节各种细胞对压力的反应中的关键作用，例如细胞死亡，细胞存活，代谢 适应和维持基因组完整性。在正常的口服上皮中，RT明显增加了水平 p53蛋白及其转录靶标和负调节剂MDM2的含量。但是，p53如何影响 辐照后口服上皮的损害和恢复仍然很少了解。基于我们 从p53敲除小鼠产生的初步数据，我们假设p53对急性DNA的响应 损害在严重辐射损伤后促进口腔上皮的再生中起着至关重要的作用。 因此，用MDM2抑制剂的处理，可增强p53依赖性信号传导专门在携带的细胞中 RT之前和期间的功能性p53蛋白会改善p53野生型口服上皮的急性损伤 不减少p53突变体HNSCC的治疗反应。我们将通过两者都检验这一假设 功能丧失和功能获取方法使用遗传学调节p53对辐射的响应 工程的小鼠模型和小分子MDM2抑制剂。 MDM2抑制对RIOM的影响将 在正常和肿瘤小鼠中进行评估。拟议研究的成功完成将提供 对p53在促进急性后促进口服上皮再生中至关重要作用的机械洞察力 辐射损伤。我们的发现将提供概念验证，以支持MDM2抑制剂的临床开发 作为RIOM的辐射保护器，以扩大RT治疗p53突变体HNSCC的治疗窗口。