Radioprotective effect of p53 against oral mucositis

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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.