Circulating Inhibitors of Endothelial Cell Growth

描述（由申请人提供）：本申请的总体目标是测试一种假设，即将血管生成抑制剂分为“直接”和“间接”血管生成抑制剂，可能有助于血管生成抑制剂治疗癌症的临床转化。“直接”血管生成抑制剂阻断血管内皮细胞增殖和/或迁移，以响应广泛的促血管生成蛋白。内皮细胞是遗传上稳定的靶标。“间接”血管生成抑制剂通过肿瘤细胞下调致癌基因的表达（如EGF受体酪氨酸激酶），或阻断该致癌基因的产物（如VEGF），或阻断该产物的受体（VEGF受体）。这些是基因上不稳定的靶标，因此“间接”血管生成抑制剂可能最终失去其功效，因为肿瘤克隆的出现产生了非抑制剂靶向的促血管生成因子。为了实现这一目标，我们将对四种“直接”血管生成抑制剂进行表征，试图修改已经在临床试验中的两种血管生成抑制剂（内皮抑素和TNP-470）的结构，以提高疗效。最近在人甲状腺癌中发现的第三种“直接”血管生成抑制剂将被纯化和测序，以用于临床应用，因为它应该扩大我们对身体如何正常使用内源性血管生成抑制剂作为肿瘤抑制蛋白的理解。第四种“直接”血管生成抑制剂血栓反应蛋白-1也在临床试验中。它作为一个主要的肿瘤抑制基因发挥作用，因为许多不同的肿瘤抑制血栓反应蛋白的表达，这是从休眠的原位非血管生成肿瘤转变为血管生成表型的先决条件。在肿瘤发生过程中抑制thbospondin -1表达的分子途径将被阐明。本研究的具体目标有助于Folkman实验室的长期未来目标，即使用“直接”血管生成抑制剂来防止血管生成开关。目前临床应用的血管生成抑制剂都是在血管生成转换后才使用的。

DESCRIPTION (provided by applicant): The overall goal of this application is to test a hypothesis that the clinical translation of angiogenesis inhibitors for treating cancer may be facilitated by categorizing them into 'direct' and 'indirect' angiogenesis inhibitors. 'Direct' angiogenesis inhibitors block vascular endothelial cell proliferation and/or migration in response to a wide spectrum of pro-angiogenic proteins. Endothelial cells are genetically stable targets. 'Indirect' angiogenesis inhibitors down-regulate expression of an oncogene by tumor cells (e.g., EGF receptor tyrosine kinase), or block a product of that oncogene, (e.g., VEGF), or block a receptor for that product, (VEGF receptor). These are genetically unstable targets, and as a result 'indirect' angiogenesis inhibitors may eventually lose their efficacy due to the emergence of tumor clones which produce pro-angiogenic factors not targeted by the inhibitor. Toward this goal, we will characterize four 'direct' angiogenesis inhibitors in an attempt to modify the structure of two of them already in clinical trials, endostatin and TNP-470, to improve efficacy. A third 'direct' angiogenesis inhibitor recently discovered in human thyroid carcinoma will be purified and sequenced for its potential application in the clinic, and because it should enlarge our understanding of how the body normally employs endogenous angiogenesis inhibitors as tumor suppressor proteins. A fourth 'direct' angiogenesis inhibitor, thrombospondin-1, is also in clinical trials. It behaves as a major tumor suppressor gene by virtue of the fact that many different tumors repress expression of thrombospondin as a pre-requisite to switching to the angiogenic phenotype from a dormant in situ, non-angiogenic tumor. The molecular pathways by which thombospondin-1 expression is repressed during tumorigenesis of carcinomas vs sarcomas will be elucidated. The Specific Aims in this study contribute to a long-term future goal of the Folkman lab, to employ 'direct' angiogenesis inhibitors to prevent the angiogenic switch. Currently, all angiogenesis inhibitors in clinical application are employed only after the angiogenic switch.