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系统。 因此，为了优化肿瘤治疗，重要的是考虑和利用这种多靶向性。 需要实验和理论方法来理清治疗中内皮细胞和肿瘤细胞之间的动态相互作用。 已知辐射诱导促血管生成生长因子（例如VEGF），其既保护肿瘤内皮细胞免受辐射杀伤又促进新血管形成。 我们假设，照射后，这些相同的因素可以导致循环内皮细胞（CEC）的生产增加，以燃料肿瘤生长。 因此，在放射治疗期间或之后使用这些因子的外源性阻断剂可以通过阻断肿瘤局部内皮细胞的存活和CEC的产生来增强放射的功效。 使用肺癌模型，我们研究了使用新型抗血管生成剂与辐射相结合来研究辐射对内皮细胞杀伤的调节。 我们建议利用和增加内皮细胞的杀伤和CEC抑制，从而提高放射治疗的疗效与小分子血管内皮生长因子受体酪氨酸激酶阻断剂目前正在临床研究。 VEGFR抑制剂将在放疗的同时和放疗后进行检测。 为此，我们将在体内和体外研究照射后促血管生成因子的时间依赖性表达。 我们还将检查以下的全基因组阵列响应：1）在不含所研究的抗血管生成药物的照射后不同肿瘤细胞区室（例如内皮细胞区室和肿瘤细胞区室），以及另外，2）在每个VEGF和VEGF-酪氨酸激酶抑制剂扰动后的内皮细胞区室。 将通过成像跟踪肿瘤血管响应于治疗的重构和消退。 由于现在认识到骨髓中产生的内皮细胞循环并被募集到损伤部位，因此将研究CEC的水平以确定这些治疗后肿瘤反应中原位内皮细胞与循环内皮细胞的相对作用。 为了确定不同肿瘤区室对治疗反应的相互影响，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。 肺癌模型被用于本研究中，因为肺癌中的放化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.