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: 6733486
• 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/6733486
• 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）：肿瘤微脉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的细胞毒性作用通过 PI3K/Akt 信号通路的激活而减弱。我们发现电离辐射会诱导 PI3K/Akt 的激活，进而在放射治疗期间调节内皮细胞的活力。抑制该信号通路可增强辐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。本研究的目标是研究电离辐射激活 PI3K/Akt 信号通路的机制。这项研究将带来潜在的新分子治疗靶点。我们的总体目标是将这种治疗策略纳入临床试验。因此，我们将研究该信号转导途径的抑制剂，这些抑制剂是用于临床试验的管道化合物。提出的具体目标将基础研究和转化研究结合起来，旨在开发治疗癌症的新策略。我们假设肿瘤微血管中辐射诱导的 PI3K/Akt 信号传导激活是通过 3 种潜在机制启动的：1）配体介导的 RTK 激活； 2）通过辐射直接激活RTK；和/或3)蛋白质酪氨酸磷酸酶的失活。这些机制并不相互排斥，并且可能各自有助于 PI3K/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 PI3K/Akt 通路激活中的作用。在具体目标 2 中，我们将确定蛋白酪氨酸磷酸酶 (PTP) 失活在辐射诱导的 PI3K/Akt 信号通路激活中的作用。在具体目标 3 中，我们将确定增强放射线对肿瘤血管内皮细胞毒性作用的 TKI 的生物活性剂量。我们将确定分子靶标，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敏化的新分子靶标。此外，我们还将描述用于临床方案开发的管线 TKI 的特征。这项调查的意义在于生活质量；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，可以提高器官保存和治愈率。