Vascular Normalization: Rolse of Perivascular Cells

抗血管内皮生长因子（VEGF）抗体贝伐单抗（Avastin）的批准， 第一种抗血管生成剂预示着实体瘤治疗的新时代，但也提出了许多问题， to how to optimally最佳use these agents代理.在目前的补助金期间，我们试图解决一个 抗血管生成治疗中一个明显的悖论--抗血管生成剂（其破坏肿瘤 血管）增强细胞毒性疗法（其需要血管来递送药物或 氧气）？我们已经发现，抗血管生成治疗可以使异常结构“正常化”， 肿瘤血管的功能，使它们更有效地输送治疗剂。我们还 发现放疗对原位生长的胶质母细胞瘤（一种脑肿瘤）具有增强作用 当它在“正常化窗口”内给予时-在抗血管生成治疗期间的一段时间， 血管功能短暂改善。此外，我们的数据表明，血管周围（壁）细胞， 募集使肿瘤血管稳定。这些挑衅性的发现得到了其他研究机构数据的支持。 实验室和我们的临床数据，提出了两个关键问题，我们建议解决：（i）什么 其他抗血管生成剂使肿瘤血管正常化的程度和持续时间 正在临床上接受测试以及（ii）促进血管周围细胞募集的策略也 改善血管功能和增强对细胞毒性疗法的反应？使用我们建立的临床前 模型，我们将调查目前在临床试验中使用的药物的反应！我们将开始 比较低分子量酪氨酸激酶抑制剂与 产生的抗体。已知这些药剂在它们的VEGF和血小板衍生物的程度上不同。 生长因子（PDGF）信号抑制（Aim 1）。然后，我们将尝试扩展归一化窗口 这些药物通过过表达Ang-1（Aim 2）调节Tie 2途径产生。最后我们 将联合收割机VEGF阻断与增强的PDGF受体β信号传导相结合，以改善血管周围细胞 覆盖肿瘤血管，增强肿瘤血管功能和对放射治疗的反应（目的3）。 使用这些新策略，我们寻求克服阻碍治疗药物递送的生理障碍。 药物治疗实体瘤，并与医生合作，开发改进的，临床相关的抗肿瘤药物， 血管生成治疗策略。

The approval of the anti-vascularendothelial growth factor (VEGF) antibody, bevacizumab (Avastin), as the first anti-angiogenic agent heralds a new era in the treatment of solid tumors, but raises many questions as to how to optimally use these agents. During the current grant period, we have attempted to resolve an apparent paradox in anti-angiogenic therapy - how can an anti-angiogenic agent (which destroys tumor vessels) enhance the outcome of cytotoxictherapy (which requires blood vessels for the delivery of drugs or oxygen)? We have discovered that anti-angiogenic treatment can "normalize" the abnormal structure and function of tumor vessels, making them more efficient for the delivery of therapeutic agents. We have also found that radiotherapy has an enhanced effect against orthotopically grown glioblastoma (a brain tumor) when it is given within the "normalization window" - a period during anti-angiogenic treatment when vascular function transiently improves. Furthermore, our data indicate that perivascular (mural) cell recruitment stabilizes tumor blood vessels. These provocative findings, supported by data from other laboratories and by our clinical data, raise two critical questions which we propose to address: (i) to what extent, and for how long, is the tumor vasculature normalized by other anti-angiogenic agents that are currently being tested in the clinic? And (ii) do strategies which facilitate perivascular cell recruitment also improve vascular function and enhance response to cytotoxic therapies? Using our established preclinical models, we will investigate the response to agents currently in use in clinical trials! We will begin by comparing the vascular normalization produced by low-molecular-weight tyrosine kinase inhibitors with that produced by antibodies. These agents are known to vary in their degree of VEGF and platelet derived growth factor (PDGF) signal inhibition (Aim 1). We will then attempt to extend the normalization window produced by these agents by modulating the Tie2 pathway via overexpression of Ang-1 (Aim 2). Finally, we will combine VEGF blockade with enhanced PDGF receptor-psignaling in order to improve perivascular cell coverage of tumor vessels and enhance tumor vascular function and response to radiotherapy (Aim 3). Using these new strategies, we seek to overcome physiological barriers that impede delivery of therapeutic agents to solid tumors, and to collaborate with physicians to develop improved, clinically relevant anti- angiogenic treatment strategies.