HIF genes in head and neck cancer radiotherapy

描述（由申请人提供）：头颈癌是五大最常见的恶性肿瘤之一。头颈部肿瘤治疗的主要问题之一是局部控制和易复发。在这项拨款申请中，我们提议检验一个可能显著改善H&N癌放疗的假设。该项目的长期目标是描述头颈癌放疗期间所谓的“主开关”：缺氧诱导因子（HIF）基因的状态，并利用这些知识获得潜在的治疗收益。我们的项目假设hif -1和2基因在决定头颈部（H&N）癌症对放疗的反应中起关键作用，抑制hif -1和2活性可以提高H&N癌症放疗的疗效。我们的项目是基于以往的研究，表明缺氧和hif -1和hif - 2因素在头颈部肿瘤放疗预后中起重要作用。此外，基于我们的新数据表明，放疗独立于缺氧激活HIF因子，通过产生瘤内一氧化氮，可以稳定HIF基因的α亚基。我们将利用新型分子成像和转基因小鼠方法，在临床前头颈癌模型中系统地表征辐射诱导的HIF-1和HIF-2基因激活。具体来说，我们将研究特定一氧化氮合酶基因在辐射诱导的hif -1和hif - 2激活中的作用（specific aim 1）。此外，我们将试图破译一氧化氮在头颈癌放疗中介导辐射诱导的hif -1和hif - 2激活的分子机制（Specific aim 2）。最后，我们将评估这两个因素在头颈癌放疗后生存率中的相对重要性（Specific Aim 3）。这些研究将为辐射诱导HIF基因活化的生物学机制提供重要见解，并评估在头颈癌放疗期间抑制这两个因子的效果。

DESCRIPTION (provided by applicant): Head and neck cancer is one of the top five most common forms of malignancy. One of main problems in head and neck cancer treatment is local regional control and frequent recurrence. In this grant application, we propose to examine a hypothesis that may significantly improve the radiotherapy of H&N cancer. The long-term objective of this project is to characterize the status of the so-called "master switches": hypoxia-inducible factor (HIF) genes, during radiotherapy of head and neck cancer and to exploit such knowledge for potential therapeutic gain. The hypothesis of our project is that HIF-1&2 genes play key roles in determining head and neck (H&N) cancer responses to radiotherapy, and that inhibiting HIF-1&2 activities can enhance the efficacy of H&N cancer radiotherapy. Our project is based on previous studies indicating that hypoxia and both of the HIF-1&2 factors play important roles in determining prognosis of head and neck cancer radiotherapy. In addition, it is based on our new data that indicated HIF factors were activated by radiotherapy independent of hypoxia through the generation of intratumoral nitric oxide, which can stabilize the alpha subunits of the HIF genes. We will conduct experiments to systematically characterize radiation-induced HIF-1 and HIF-2 gene activation in preclinical head and neck cancer models by use of novel molecular imaging and transgenic mouse approaches. Specifically, we will examine the roles of specific nitric oxide synthase genes in radiation-induced HIF-1&2 activation (Specific aim 1). In addition, we will attempt to decipher the molecular mechanism through which nitric oxide mediates radiation-induced HIF-1&2 activation in head and neck cancer radiotherapy (Specific aim 2). Finally, we will evaluate the relative importance of these two factors in head and neck cancer survival after radiotherapy (Specific Aim 3). The proposed studies should provide important insights into the biological mechanisms of radiation-induced activation of the HIF genes and evaluate the efficacy for inhibiting these two factors during head and neck cancer radiotherapy.