Modulation of Radiation Action on Endothelial Cells

描述(申请人提供)：放射治疗不仅作用于肿瘤细胞，也作用于肿瘤血管。因此，为了优化肿瘤治疗，重要的是要考虑和开发这种多靶点能力。需要实验和理论两种方法来理清治疗中的内皮细胞和肿瘤细胞之间的动态相互作用。辐射可诱导促血管生成生长因子(如血管内皮生长因子)，既能保护肿瘤内皮细胞免受辐射损伤，又能促进新生血管形成。我们假设，在照射后，这些相同的因素可以导致循环内皮细胞(CECs)的产生增加，以促进肿瘤的生长。因此，在放射治疗期间或之后使用这些因子的外源性阻滞剂可能会通过阻断肿瘤局部内皮细胞的存活和CEC的产生来增强放射治疗的疗效。利用肺癌模型，我们研究了新型抗血管生成剂与辐射联合使用来研究辐射对内皮细胞杀伤的调节作用。我们建议开发和增加内皮细胞杀伤和CEC抑制，从而通过目前正在临床研究的小分子血管内皮生长因子受体酪氨酸激酶阻滞剂来提高放射疗效。VEGFR抑制剂将在放射治疗的同时和之后进行测试。为此，我们将在体内和体外研究辐射后促血管生成因子的时间依赖性表达。我们还将检查全基因组阵列的响应：1)不同的肿瘤细胞隔间(例如，内皮细胞和肿瘤细胞隔间)在没有研究中的抗血管生成药物的照射下，以及2)每种血管内皮生长因子和VEGFR-酪氨酸激酶抑制剂扰动后的内皮细胞隔间。治疗后肿瘤血管的重建和消退将通过成像进行追踪。由于现在已经认识到，在骨髓中产生的内皮细胞在骨髓循环中并被招募到损伤部位，因此将对CEC水平进行研究，以确定在这些治疗后在位和循环内皮细胞在肿瘤反应中的相对作用。为了确定不同肿瘤间隔对治疗反应的相互影响，将扩展Pi的肿瘤/血管生长的理论模型，该模型考虑了肿瘤细胞和内皮细胞之间的串扰，并将纳入我们的经验数据。该数学模型有助于将机制(例如，肿瘤与内皮细胞杀伤的比率)与治疗反应相关联。本研究使用肺癌模型，因为肺癌的化疗和放射治疗迫切需要有效的辅助治疗。因此，这些研究将具有重要的翻译和科学意义。

DESCRIPTION (provided by applicant): Radiation therapy acts not only on tumor cells but also on the tumor vasculature. Thus, to optimize tumor treatment it is important that this multi-targetability be considered and exploited. Both experimental and theoretical methods are needed to sort out the dynamic interactions between the endothelial and tumor cells under treatment. Radiation is known to induce pro-angiogenic growth factors (e.g. VEGF) that both protect tumor endothelial cells from radiation killing and promote neovascularization. We hypothesize that following irradiation these same factors can lead to increased production of circulating endothelial cells (CECs) to fuel tumor growth. Thus, the use of exogenous blockers of these factors during or after radiation treatment may enhance the efficacy of radiation by blocking both survival of endothelial cells local to the tumor and the production of CECs. Using lung cancer models, we examine the use of novel antiangiogenic agents in combination with radiation to study the modulation of radiation killing of endothelial cells. We propose to exploit and increase endothelial killing and CEC repression and thereby enhance radiation efficacy by treatment with small-molecule VEGF receptor tyrosine kinase blockers currently under clinical study. The VEGFR inhibitors will be tested concurrently with and subsequent to radiation. To this end, we will investigate, in vivo and in vitro, the time-dependent expression of the pro-angiogenic factors following irradiation. We will also examine genome-wide array response of: 1) different tumor cell compartments (e.g. the endothelial-cell and tumor-cell compartments) following irradiation w/o the antiangiogenics under study, and additionally, 2) the endothelial-cell compartment following each VEGF and VEGFR-tyrosine kinase inhibitor perturbation. The restructuring and regression of tumor vascular in response to treatment will be tracked by imaging. Since it is now recognized mat endothelial cells arising in the bone marrow circulate and are recruited to sites of injury, levels of CECs will be studied to determine the relative roles of on-site vs. circulating endothelial cells in tumor response following these treatments. To determine the reciprocal influence of the different tumor compartments to therapeutic response, 'the Pi's theoretical model of tumor/vascular growth that takes into account cross-talk between tumor-cells and endothelial cells will be extended and our empirical data will be incorporated. This mathematical model is instrumental for associating mechanistics (e.g. ratios of tumor to endothelial cell killing) with therapeutic response. Lung cancer models are used in this investigation because effective adjuvant treatments for chemoradiotherapy in lung cancer are badly needed. These studies will therefore have significant translational as well as scientific relevance.