Modulation of Radiation Action on Endothelial Cells

内皮细胞辐射作用的调节

• 批准号: 7125992
• 负责人: Lynn Hlatky
• 金额: $ 25.46万
• 依托单位: STEWARD ST. ELIZABETH'S MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-23 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7125992
• 关键词: SCID mouse; angiogenesis; angiogenesis inhibitors; cell cell interaction; combination cancer therapy; growth factor receptors; laboratory mouse; lung neoplasms; mathematical model; microarray technology; neoplasm /cancer blood supply; neoplasm /cancer radiation therapy; nonhuman therapy evaluation; vascular endothelial growth factors; vascular endothelium

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.

描述（由申请人提供）：放射疗法不仅对肿瘤细胞，而且还作用于肿瘤脉管系统上。 因此，要优化肿瘤治疗，重要的是要考虑和利用这种多目标。 需要实验方法和理论方法来整理治疗中内皮细胞和肿瘤细胞之间的动态相互作用。 已知辐射会诱导促血管生长因子（例如VEGF），这些因子既保护肿瘤内皮细胞免受辐射杀死并促进新生血管形成。 我们假设辐照后，这些相同的因素可能导致循环内皮细胞（CEC）的产生增加，从而促进肿瘤生长。 因此，在放射治疗期间或之后，使用这些因素的外源阻滞剂可以通过阻止局部肿瘤的内皮细胞的存活和CEC的产生来增强辐射的疗效。 使用肺癌模型，我们检查了新型抗血管生成剂与辐射的使用，以研究内皮细胞辐射杀死的调节。 我们建议利用和增加内皮杀戮和CEC抑制，从而通过使用临床研究中的小分子VEGF受体酪氨酸激酶阻滞剂进行治疗来提高辐射功效。 VEGFR抑制剂将与辐射同时进行测试。 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。 我们还将检查以下基因组的阵列响应：1）辐射后，与正在研究的抗血管生成的辐射后，不同的肿瘤细胞室（例如内皮细胞和肿瘤细胞室），以及2）每个素食性素食室和蔬菜 - 素食型和蔬菜型毒素基因酶抗抑制剂。 肿瘤血管对治疗的重组和回归将通过成像跟踪。 由于现在已经识别出在骨髓循环中产生并募集到损伤部位的MAT内皮细胞，因此将研究CEC的水平，以确定这些处理后的现场与循环内皮细胞在肿瘤反应中的相对作用。 为了确定不同肿瘤室对治疗反应的相互影响，“ PI的肿瘤/血管生长理论模型将考虑肿瘤细胞和内皮细胞之间的串扰，并将我们的经验数据纳入其中。 该数学模型具有关联机构（例如肿瘤与内皮细胞杀伤的比率）与治疗反应的工具。 该研究中使用了肺癌模型，因为急需进行化学放射治疗的有效辅助治疗。 因此，这些研究将具有显着的转化和科学意义。