Circulating Inhibitors of Endothelial Cell Growth

描述(申请人提供)：本申请的总体目标是测试这样一个假设，即通过将用于治疗癌症的血管生成抑制剂分类为直接的和间接的血管生成抑制剂，可以促进它们的临床翻译。“直接”血管生成抑制剂阻止血管内皮细胞的增殖和/或迁移，以响应广泛的促血管生成蛋白。内皮细胞在遗传上是稳定的靶点。“间接”血管生成抑制剂下调肿瘤细胞对癌基因的表达(如EGF受体酪氨酸激酶)，或阻断该癌基因的产物(如血管内皮生长因子)，或阻断该产物的受体(血管内皮生长因子受体)。这些都是遗传上不稳定的靶点，因此，由于肿瘤克隆的出现，间接的血管生成抑制剂可能最终会失去疗效，这些克隆产生的促血管生成因子不是抑制剂的靶点。为了实现这一目标，我们将鉴定四种直接的血管生成抑制剂，试图修改其中两种已经在临床试验中的内皮抑素和TNP-470的结构，以提高疗效。最近在人类甲状腺癌中发现的第三种直接血管生成抑制物将被提纯和测序，以便在临床上潜在应用，因为它将扩大我们对体内正常情况下如何使用内源性血管生成抑制物作为肿瘤抑制蛋白的理解。第四种“直接”血管生成抑制剂--凝血酶敏感蛋白-1也在临床试验中。它是一种主要的肿瘤抑制基因，因为许多不同的肿瘤抑制凝血酶反应蛋白的表达，这是从原位休眠的、非血管生成的肿瘤转变为血管生成表型的先决条件。在癌症和肉瘤的发生过程中，Tombospondin-1表达被抑制的分子途径将被阐明。这项研究的具体目标有助于Folkman实验室未来的长期目标，即使用“直接”血管生成抑制剂来防止血管生成开关。目前，所有临床应用的血管生成抑制剂都是在血管生成转换后才开始使用。

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.