Radioprotective effect of p53 against oral mucositis

摘要 头颈部鳞状细胞癌（HNSCC）是第六大常见癌症 国际吧全球癌症观察站预测，到2030年， 每年新增病例约108万例。放射治疗（RT）在治疗HNSCC中起着不可或缺的作用; 然而，头部和颈部RT与口腔粘膜中的显著毒性相关。这种毒性被称为 辐射诱发的口腔粘膜炎（RIOM），可导致阿片类药物使用、口服摄入量减少/营养状况差， 需要中断治疗，所有这些都与HNSCC患者的不良结局相关。作为 目前RIOM的治疗选择是有限的，开发新的辐射防护剂的需求未得到满足， 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。本报告的总体目标 应用的目的是确定p53在调节RIOM中的作用。p53基因在80%以上的人中是突变的。 HNSCC是乳头瘤病毒阴性的HNSCC，但其在邻近正常组织中保持野生型。p53蛋白在肿瘤中起着重要作用。 在调节对应激的各种细胞反应如细胞死亡、细胞存活、代谢和免疫应答中起关键作用。 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 p53蛋白及其转录靶点和负调节因子Mdm 2的表达。p53如何影响 辐照后口腔上皮的损伤和恢复仍然知之甚少。基于我们 从p53基因敲除小鼠产生的初步数据，我们假设p53对急性DNA损伤的反应， 损伤在促进严重辐射损伤后口腔上皮的再生中起关键作用。 因此，用Mdm 2抑制剂治疗可以特异性地增强携带p53的细胞中的p53依赖性信号传导， RT前和RT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 而不降低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一假设： 利用基因工程技术调节p53对辐射反应的功能丧失和功能获得方法 工程小鼠模型和小分子Mdm 2抑制剂。Mdm 2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 p53在促进口腔上皮细胞急性损伤后再生中的关键作用的机制研究 辐射损伤我们的研究结果将为Mdm 2抑制剂的临床开发提供概念验证 作为RIOM的辐射保护剂，以拓宽RT治疗p53突变型HNSCC的治疗窗。

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.