Circulating Inhibitors of Endothelial Cell Growth

内皮细胞生长的循环抑制剂

• 批准号: 7348329
• 负责人: MICHAEL KLAGSBRUN
• 金额: $ 31.11万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-16 至 2009-08-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7348329
• 关键词: Angiogenesis Inhibitors; Angiogenic Factor; Angiogenic Proteins; Angiogenic Switch; Carcinoma; Cell Proliferation; Clinic; Clinical; Clinical Trials; Endostatins; Endothelial Cells; Epidermal Growth Factor Receptor; Future; Goals; Human; Immigration; In Situ; Malignant Neoplasms; Molecular; Molecular Weight; Oncogene Proteins; Oncogenes; Pathway interactions; Phenotype; Receptor Protein-Tyrosine Kinases; Regulation; Structure; TNP470; Testing; Thrombospondin 1; Thyroid carcinoma; Translations; Tumor Suppressor Genes; Tumor Suppressor Proteins; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; cell growth; clinical application; improved; inhibitor/antagonist; neoplastic cell; neurotoxicity; novel; prevent; receptor; response; sarcoma; tumor; tumorigenesis

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.

描述（由申请人提供）：本申请的总体目标是测试这样的假设：通过将血管生成抑制剂分类为“直接”和“间接”血管生成抑制剂，可以促进用于治疗癌症的血管生成抑制剂的临床转化。 “直接”血管生成抑制剂可阻断血管内皮细胞响应多种促血管生成蛋白而增殖和/或迁移。 Endothelial cells are genetically stable targets. “间接”血管生成抑制剂下调肿瘤细胞癌基因的表达（例如，EGF受体酪氨酸激酶），或阻断该癌基因的产物（例如，VEGF），或阻断该产物的受体（VEGF受体）。这些是遗传上不稳定的靶标，因此“间接”血管生成抑制剂可能最终因肿瘤克隆的出现而失去功效，这些克隆产生的促血管生成因子不是抑制剂的目标。为了实现这一目标，我们将表征四种“直接”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”血管生成抑制剂将被纯化并测序，以了解其在临床中的潜在应用，并且因为它应该扩大我们对身体通常如何利用内源性血管生成抑制剂作为肿瘤抑制蛋白的理解。 A fourth 'direct' angiogenesis inhibitor, thrombospondin-1, is also in clinical trials.它充当主要的肿瘤抑制基因，因为许多不同的肿瘤抑制血小板反应蛋白的表达，这是从原位休眠、非血管生成肿瘤转变为血管生成表型的先决条件。 The molecular pathways by which thombospondin-1 expression is repressed during tumorigenesis of carcinomas vs sarcomas will be elucidated.这项研究的具体目标有助于福克曼实验室的长期未来目标，即采用“直接”血管生成抑制剂来防止血管生成转换。 Currently, all angiogenesis inhibitors in clinical application are employed only after the angiogenic switch.

项目成果

Angiogenesis Research: Guidelines for Translation to Clinical Application

• DOI: 10.1055/s-0037-1616197
• 发表时间: 2001-07
• 期刊: Thrombosis and Haemostasis
• 影响因子: 6.7
• 作者: J. Folkman;T. Browder;J. Palmblad

Antitumor activity of endostatin against carcinogen-induced rat primary mammary tumors.

内皮抑素对致癌物诱导的大鼠原发性乳腺肿瘤的抗肿瘤活性。

• 发表时间: 2000
• 期刊: Cancer research.
• 作者: Perletti,G;Concari,P;Giardini,R;Marras,E;Piccinini,F;Folkman,J;Chen,L
• 通讯作者: Chen,L

Tumor development under angiogenic signaling: a dynamical theory of tumor growth, treatment response, and postvascular dormancy.

• 发表时间: 1999-10
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: P. Hahnfeldt;D. Panigrahy;J. Folkman;L. Hlatky

The generation of endostatin is mediated by elastase.

• 发表时间: 1999-12
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Wei Wen;M. Moses;D. Wiederschain;J. Arbiser;J. Folkman

Endostatin therapy reveals a U-shaped curve for antitumor activity.

内皮抑素治疗显示抗肿瘤活性呈 U 形曲线。

• DOI: 10.1038/sj.cgt.7700938
• 发表时间: 2006
• 期刊: Cancer gene therapy.
• 作者: TjinThamSjin,RM;Naspinski,J;Birsner,AE;Li,C;Chan,R;Lo,K-M;Gillies,S;Zurakowski,D;Folkman,J;Samulski,J;Javaherian,K
• 通讯作者: Javaherian,K