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.

摘要 头颈部鳞状细胞癌(HNSCC)是第六大常见癌症 全世界。全球癌症观察站预测，到2030年，年发病率将增加30% 每年约有108万个新病例。放射治疗(RT)在HNSCC的治疗中起着不可或缺的作用； 然而，头颈部放疗与口腔粘膜的显著毒性有关。这种毒性被称为 放射性口腔粘膜炎(Riom)，可导致阿片类药物的使用，减少口服摄入量/营养状况差，以及 需要中断治疗，所有这些都与HNSCC患者更糟糕的结局相关。AS 目前Riom的治疗选择有限，但开发新型放射防护剂的需求尚未得到满足 将拓宽头颈部放疗的治疗窗口。我们的长期目标是开发新的治疗方法 在不牺牲肿瘤控制的情况下预防或减少Riom的策略。这样做的总体目标是 应用是确定P53在调节Riom中的作用。P53基因在80%的人类中发生突变 乳头瘤病毒阴性的HNSCC，但在邻近正常组织中仍为野生型。P53蛋白扮演着一个 在调节细胞对应激的各种反应中起关键作用，如细胞死亡、细胞存活、代谢 适应和维持基因组的完整性。在正常口腔上皮中，RT显著增加其水平 P53蛋白及其转录靶点和负调控因子MDM2的表达。然而，P53如何影响 照射后口腔上皮的损伤和恢复仍然知之甚少。基于我们的 从p53基因敲除小鼠产生的初步数据，我们假设p53对急性DNA的反应 损伤在促进严重辐射损伤后口腔上皮再生中起着至关重要的作用。 因此，用MDM2抑制剂治疗，可以增强P53依赖的信号转导，特别是在含有 放疗前后功能性P53蛋白对P53野生型口腔上皮急性损伤的改善作用 而不降低p53突变型HNSCC的治疗效果。我们将通过以下两种方法来检验这一假设 利用遗传学方法调节P53对辐射的反应的功能丧失和功能获得途径 转基因小鼠模型和小分子MDM2抑制剂。MDM2抑制对Riom Will的影响 在正常和荷瘤小鼠身上进行评估。成功完成拟议的研究将提供 急性口腔黏膜损伤后P53在促进口腔上皮再生中的重要作用 辐射损伤。我们的发现将为MDM2抑制剂的临床开发提供概念验证 作为Riom的辐射保护剂，拓宽RT治疗p53突变HNSCC的治疗窗口。