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:
  • 金额:
    $ 50.68万
  • 依托单位:
  • 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

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.
摘要

项目成果

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Chang-Lung Lee其他文献

Chang-Lung Lee的其他文献

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{{ truncateString('Chang-Lung Lee', 18)}}的其他基金

Inhibition of CaMKK2 sensitizes rectal cancers to radiation therapy
CaMKK2 的抑制使直肠癌对放射治疗敏感
  • 批准号:
    10312803
  • 财政年份:
    2021
  • 资助金额:
    $ 50.68万
  • 项目类别:
Inhibition of CaMKK2 sensitizes rectal cancers to radiation therapy
CaMKK2 的抑制使直肠癌对放射治疗敏感
  • 批准号:
    10112586
  • 财政年份:
    2021
  • 资助金额:
    $ 50.68万
  • 项目类别:
Minimizing the risk of therapy-related myeloid neoplasms by inhibiting genotoxic stress-induced expansion of leukemia-initiating cells with p53 mutations
通过抑制基因毒性应激诱导的 p53 突变白血病起始细胞的扩增,最大限度地降低治疗相关的骨髓肿瘤的风险
  • 批准号:
    10113420
  • 财政年份:
    2020
  • 资助金额:
    $ 50.68万
  • 项目类别:
Minimizing the risk of therapy-related myeloid neoplasms by inhibiting genotoxic stress-induced expansion of leukemia-initiating cells with p53 mutations
通过抑制基因毒性应激诱导的 p53 突变白血病起始细胞的扩增,最大限度地降低治疗相关的骨髓肿瘤的风险
  • 批准号:
    10310505
  • 财政年份:
    2020
  • 资助金额:
    $ 50.68万
  • 项目类别:
Dissecting mechanism(s) by which ionizing radiation promotes clonal expansion of premalignant cells in the thymus
剖析电离辐射促进胸腺癌前细胞克隆扩张的机制
  • 批准号:
    9353350
  • 财政年份:
    2016
  • 资助金额:
    $ 50.68万
  • 项目类别:

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