HIF genes in head and neck cancer radiotherapy

描述(申请人提供)：头颈癌是最常见的五种恶性肿瘤之一。头颈部肿瘤治疗的主要问题之一是局部区域控制和复发频繁。在这项拨款申请中，我们建议检验一项可能显著改善H&N癌放射治疗的假说。该项目的长期目标是确定头颈癌放射治疗过程中所谓的“主开关”：缺氧诱导因子(HIF)基因的状态，并利用这些知识来获得潜在的治疗收益。我们的假设是，HIF-1和HIF-2基因在决定头颈部肿瘤对放射治疗的反应中起关键作用，抑制HIF-1和HIF-2活性可以提高头颈部肿瘤放射治疗的疗效。我们的项目是基于先前的研究，表明缺氧和HIF-1和HIF-2在头颈部肿瘤放射治疗的预后中起着重要的作用。此外，基于我们的新数据，表明HIF因子是通过肿瘤内一氧化氮的产生而被放射治疗激活的，这种激活不依赖于低氧，而一氧化氮可以稳定HIF基因的α亚基。我们将通过新的分子成像和转基因小鼠的方法，系统地研究辐射诱导的HIF-1和HIF-2基因在临床前头颈癌模型中的激活。具体地说，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(特定目标1)。此外，我们将尝试破译一氧化氮在头颈癌放射治疗中介导辐射诱导的HIF-1和2激活的分子机制(特定目标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(特定目标3)。这项研究将对辐射诱导HIF基因激活的生物学机制提供重要的见解，并评估在头颈部肿瘤放射治疗中抑制这两个因素的效果。 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，以加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.