Modulation of Radiation Action on Endothelial Cells

描述（由申请人提供）：放射治疗不仅作用于肿瘤细胞，而且作用于肿瘤血管。因此，为了优化肿瘤治疗，考虑和利用这种多靶标性是很重要的。需要实验和理论两方面的方法来梳理内皮细胞和肿瘤细胞在治疗过程中的动态相互作用。已知辐射可诱导促血管生成生长因子（如VEGF），其既保护肿瘤内皮细胞免受辐射杀伤，又促进新生血管形成。我们假设辐照后，这些相同的因素可以导致循环内皮细胞（CECs）的产生增加，从而促进肿瘤的生长。因此，在放疗期间或放疗后使用这些因子的外源性阻滞剂可以通过阻断肿瘤局部内皮细胞的存活和CECs的产生来增强放疗的疗效。利用肺癌模型，我们研究了新型抗血管生成药物与辐射联合使用，以研究辐射杀死内皮细胞的调节。我们建议利用目前正在临床研究的小分子VEGF受体酪氨酸激酶阻滞剂来开发和增加内皮细胞杀伤和CEC抑制，从而提高放疗疗效。VEGFR抑制剂将在放疗的同时和放疗后进行测试。为此，我们将在体内和体外研究辐照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反应：1)不同的肿瘤细胞区室（如内皮细胞和肿瘤细胞区室）在无抗血管生成药物照射后的反应，另外，2)内皮细胞区室在每次VEGF和vegfr -酪氨酸激酶抑制剂扰动后的反应。肿瘤血管在治疗后的重建和消退将通过影像学追踪。由于现在已经认识到内皮细胞在骨髓循环中产生并被招募到损伤部位，因此将研究CECs的水平，以确定这些治疗后原位内皮细胞与循环内皮细胞在肿瘤反应中的相对作用。为了确定不同肿瘤区室对治疗反应的相互影响，Pi的肿瘤/血管生长理论模型将得到扩展，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（如肿瘤与内皮细胞杀伤的比率）与治疗反应联系起来。由于肺癌放化疗迫切需要有效的辅助治疗，因此本研究采用肺癌模型。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.