Vascular Normalization: Rolse of Perivascular Cells

批准抗血管内皮细胞生长因子抗体贝伐单抗(阿瓦斯丁)作为 第一种抗血管生成剂预示着实体肿瘤治疗的新纪元，但也引发了许多问题，如 如何以最佳方式使用这些药剂。在当前的授权期内，我们已尝试解决 抗血管生成治疗中的明显悖论--一种抗血管生成剂(破坏肿瘤)如何 血管)加强细胞毒治疗的结果(需要血管输送药物或 氧气)？我们发现，抗血管生成治疗可以使异常结构和 提高肿瘤血管的功能，使其更有效地输送治疗剂。我们还有 发现放射治疗对原位生长的胶质母细胞瘤(一种脑瘤)有增强作用 当在“正常化窗口”内给药时--抗血管生成治疗期间 血管功能暂时改善。此外，我们的数据表明血管周围(壁细胞)细胞 募集能稳定肿瘤血管。这些具有挑衅性的发现得到了来自其他机构的数据的支持 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)解决什么 肿瘤血管被其他抗血管生成药物正常化的程度和持续时间有多长 目前正在诊所接受检测？和(Ii)促进血管周围细胞募集的DO策略 改善血管功能，增强对细胞毒治疗的反应？利用我们已建立的临床前阶段 模型，我们将调查目前在临床试验中使用的药物的反应！我们将从 比较低分子酪氨酸激酶抑制剂和低分子酪氨酸激酶抑制剂产生的血管正常化 这是由抗体产生的。众所周知，这些药物的血管内皮生长因子和血小板衍生程度各不相同。 生长因子(PDGF)信号抑制(目标1)。然后，我们将尝试延长标准化窗口 由这些药物通过过度表达Ang-1来调节Tie2途径而产生(目标2)。最后，我们 将血管内皮生长因子拮抗剂与增强的PDGF受体信号转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(目标3)。 使用这些新策略，我们寻求克服阻碍治疗药物传递的生理障碍。 实体肿瘤的药物，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.