HIF genes in head and neck cancer radiotherapy

描述（由申请人提供）：头颈癌是五种最常见的恶性肿瘤之一。头颈部恶性肿瘤治疗的主要问题之一是局部区域控制和复发率高。在这项资助申请中，我们提出了一个假设，可以显着改善H&N癌症的放射治疗。该项目的长期目标是确定头颈部癌症放射治疗期间所谓的“主开关”：缺氧诱导因子基因的状况，并利用这些知识获得潜在的治疗收益。我们的研究假设HIF-1和HIF-2基因在决定头颈癌放疗反应中起关键作用，抑制HIF-1和HIF-2活性可以提高头颈癌放疗的疗效。本课题基于既往研究表明缺氧和HIF-1、HIF-2因子在决定头颈部肿瘤放疗预后中起重要作用。 此外，它是基于我们的新数据，表明HIF因子被放射治疗激活，而不依赖于缺氧，通过产生肿瘤内一氧化氮，这可以稳定HIF基因的α亚基。我们将通过使用新型分子成像和转基因小鼠方法进行实验，系统地表征辐射诱导的HIF-1和HIF-2基因在临床前头颈癌模型中的激活。具体来说，我们将研究特定的一氧化氮合酶基因在辐射诱导的HIF-1和2激活中的作用（具体目标1）。 此外，我们将尝试破译头颈癌放疗中一氧化氮介导辐射诱导的HIF-1和2激活的分子机制（具体目标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（具体目标3）。拟议的研究应提供重要的见解辐射诱导激活的HIF基因的生物学机制，并评估在头颈部癌症放疗抑制这两个因素的疗效。 公共卫生相关性：本项目研究HIF基因参与头颈癌放射治疗的机制。它可能提供新的见解，允许开发新的治疗方法，可以增强当前的头颈癌治疗。

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. PUBLIC HEALTH RELEVANCE: This project studies the mechanism of the involvement of the HIF genes in radiotherapy treatment of head and neck cancer. It may provide new insights that allow for the development of new therapeutics that can enhance current head and neck cancer therapy.