FLK1 Signaling Protects Tumor Vasculature from Radiation

FLK1 信号传导保护肿瘤脉管系统免受辐射

• 批准号: 6852711
• 负责人: DENNIS E HALLAHAN
• 金额: $ 30.58万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6852711
• 关键词: athymic mouse; biological signal transduction; cytotoxicity; enzyme activity; free radical oxygen; ionizing radiation; kinase inhibitor; matrix assisted laser desorption ionization; neoplasm /cancer blood supply; neoplasm /cancer radiation therapy; phosphatidylinositol 3 kinase; phosphorylation; protein structure function; protein tyrosine kinase; protein tyrosine phosphatase; proteomics; radiation resistance; radiosensitizer; serine threonine protein kinase; tissue /cell culture; vascular endothelium

DESCRIPTION (provided by applicant): Tumor microvasculature is a therapeutic target in the treatment of cancer. The overall hypothesis of this translational research is that the cytotoxic effects of ionizing radiation on the tumor microvascular endothelium are attenuated by activation of the PI3K/Akt signaling pathway. We have found that ionizing radiation induces the activation of PI3K/Akt, which in turn regulates endothelial cell viability during treatment with radiotherapy. Inhibition of this signaling pathway enhances the cytotoxic effects of radiation in tumor vascular endothelium resulting in enhanced tumor control. The goals of the proposed research are to study the mechanisms by which ionizing radiation activates the PI3K/Akt signaling pathway. This research will lead to potential new molecular targets for therapy. Our overall goal is to bring this therapeutic strategy into clinical trials. We will, therefore, study inhibitors of this signal transduction pathway that are pipeline compounds for clinical trials. The proposed specific aims combine both basic and translational research with the intention of developing new strategies for the treatment of cancer. We hypothesize that radiation-induced activation of PI3K/Akt signaling in tumor microvasculature is initiated through 3 potential mechanisms: 1) ligand-mediated RTK activation; 2) direct RTK activation by radiation; and/or 3) inactivation of protein tyrosine phosphotases. These mechanisms are not mutually exclusive and may each contribute toward amplification of the PI3K/Akt signaling. In Specific Aim 1, we will determine the role of receptor tyrosine kinases in radiation-induced activation of the PI3K/Akt pathway. In Specific Aim 2, we will determine the role of protein tyrosine phosphotase (PTP) inactivation in radiation-induced activation of the PI3K/Akt signaling pathway. In Specific Aim 3, we will determine the biologically active dose of TKIs that enhance the cytotoxic effects of radiation on tumor vascular endothelium. We will identify molecular targets to improve local and regional control of cancers such as malignant gliomas and head and neck cancer. The importance of this study is that new molecular targets for radiation sensitization will be identified. Furthermore, we will characterize pipeline TKIs for clinical protocol development. The significance of this investigation is that quality of life; organ preservation and cure rates can be improved by enhancing the cytotoxic effects of localized irradiation through the use of tyrosine kinase inhibitors.

描述（由申请人提供）：肿瘤微血管系统是癌症治疗中的治疗靶点。这项转化研究的总体假设是，电离辐射对肿瘤微血管内皮细胞的细胞毒性作用通过激活PI 3 K/Akt信号通路而减弱。我们已经发现，电离辐射诱导PI 3 K/Akt的激活，这反过来又调节内皮细胞的活力，在治疗与放射治疗。抑制该信号传导途径可增强放射对肿瘤血管内皮细胞的细胞毒性作用，从而增强肿瘤控制。本研究的目的是研究电离辐射激活PI 3 K/Akt信号通路的机制。这项研究将为治疗带来潜在的新分子靶点。我们的总体目标是将这种治疗策略引入临床试验。因此，我们将研究这种信号转导途径的抑制剂，这些抑制剂是临床试验的管道化合物。拟议的具体目标联合收割机结合了基础和转化研究，旨在开发治疗癌症的新策略。我们假设肿瘤微血管中放射诱导的PI 3 K/Akt信号传导激活通过3种潜在机制启动：1）配体介导的RTK激活; 2）放射直接RTK激活;和/或3）蛋白酪氨酸磷酸酶失活。这些机制不是相互排斥的，并且可能各自有助于PI 3 K/Akt信号传导的放大。 在具体目标1中，我们将确定受体酪氨酸激酶在辐射诱导的PI 3 K/Akt通路激活中的作用。在特定目标2中，我们将确定蛋白酪氨酸磷酸酶（PTP）失活在辐射诱导的PI 3 K/Akt信号通路激活中的作用。在具体目标3中，我们将确定TKI的生物活性剂量，该剂量可增强放射对肿瘤血管内皮细胞的细胞毒性作用。我们将确定分子靶点，以改善恶性胶质瘤和头颈癌等癌症的局部和区域控制。这项研究的重要性在于，将确定辐射致敏的新分子靶点。此外，我们还将描述用于临床方案开发的管线TKI。这项研究的意义在于，通过使用酪氨酸激酶抑制剂增强局部照射的细胞毒性作用，可以提高生活质量、器官保存和治愈率。