Radioprotective effect of p53 against oral mucositis

p53对口腔粘膜炎的放射防护作用

基本信息

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
项目类别：
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

项目摘要

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 万新病例。放射治疗 (RT) 在治疗 HNSCC 中发挥着不可或缺的作用；然而，头颈放疗与口腔粘膜的显着毒性有关。这种毒性，称为放射诱发的口腔粘膜炎 (RIOM)，可导致阿片类药物的使用、口腔摄入量减少/营养状况不佳，以及治疗中断的需要，所有这些都与 HNSCC 患者的较差预后相关。作为目前 RIOM 的治疗选择有限，因此开发新型放射防护剂的需求尚未得到满足将扩大头颈放疗的治疗窗口。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。本次活动的总体目标应用的目的是定义p53在调节RIOM中的作用。 p53 基因在超过 80% 的人类中发生突变乳头瘤病毒阴性 HNSCC，但在邻近正常组织中仍保持野生型。 p53 蛋白发挥着在调节各种细胞对应激的反应中发挥着关键作用，例如细胞死亡、细胞存活、代谢适应和维持基因组完整性。在正常口腔上皮中，RT 显着提高 p53 蛋白及其转录靶标和负调节因子 Mdm2。然而，p53 如何影响照射后口腔上皮的损伤和恢复仍知之甚少。基于我们的 p53 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放射损伤后口腔上皮的再生中起着至关重要的作用。因此，用 Mdm2 抑制剂治疗可增强 p53 依赖性信号传导，特别是在含有放疗前和放疗期间的功能性 p53 蛋白将改善 p53 野生型口腔上皮的急性损伤不降低 p53 突变型 HNSCC 的治疗反应。我们将通过以下两个方面来检验这个假设利用基因功能丧失和获得功能的方法来调节 p53 对辐射的反应工程小鼠模型和小分子 Mdm2 抑制剂。 Mdm2 抑制对 RIOM 的影响将在正常和荷瘤小鼠中进行评估。成功完成拟议的研究将提供关于 p53 在促进急性口腔上皮细胞再生中的关键作用的机制见解辐射损伤。我们的研究结果将为支持 Mdm2 抑制剂的临床开发提供概念验证作为 RIOM 的放射保护剂，以扩大 RT 治疗 p53 突变型 HNSCC 的治疗窗口。