FLK1 Signaling Protects Tumor Vasculature from Radiation

描述（申请人提供）：肿瘤微血管是治疗癌症的治疗靶点。本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激活PI3K/Akt信号通路而减弱。我们发现电离辐射诱导PI3K/Akt的激活，进而调节放疗治疗期间内皮细胞的活力。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PI3K/Akt信号通路的机制。这项研究将为治疗提供潜在的新分子靶点。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，作为临床试验的管道化合物。提出的具体目标结合了基础研究和转化研究，旨在开发治疗癌症的新策略。我们假设辐射诱导的肿瘤微血管PI3K/Akt信号的激活通过3种可能的机制启动：1)配体介导的RTK激活；2)辐射直接激活RTK；和/或3)蛋白酪氨酸磷酸酶的失活。这些机制并不是相互排斥的，它们可能都有助于PI3K/Akt信号的放大。

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.