AKT pathway as a therapeutic tumor vessel target

AKT 通路作为治疗性肿瘤血管靶点

• 批准号: 7525417
• 负责人: LAURA E BENJAMIN
• 金额: $ 38.96万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7525417
• 关键词: Ablation; Angiogenesis Inhibitors; Applications Grants; Blood; Blood Vessels; Blood flow; Breast Cancer Model; Cells; Clinical; Clinical Trials; Communities; Critical Pathways; Data; Dermal; Edema; Endothelium; Estrogens; Extravasation; Feedback; Fibrin; Fibroblasts; Future; Genes; Goals; Grant; Hand; In Vitro; Inflammatory; Investigation; Laboratories; Lymphatic; Malignant Neoplasms; Mammary gland; Mediating; Molecular; Molecular Target; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Pathway interactions; Pharmacologic Substance; Phenotype; Phosphotransferases; Primary Neoplasm; Proteins; Proto-Oncogene Proteins c-akt; Public Health; Regulation; Relative (related person); Role; Route; Signal Pathway; Signal Transduction; Sirolimus; Stromal Neoplasm; Testing; Therapeutic; Thinking; TimeLine; Tissues; Tumor-Associated Vasculature; Vascular Endothelial Growth Factors; Vascular Endothelium; Vascular Permeabilities; angiogenesis; cellular targeting; chemotherapy; design; extracellular; human FRAP1 protein; in vivo; inhibitor/antagonist; mTOR Inhibitor; mTOR Signaling Pathway; malignant breast neoplasm; mouse model; neoplastic cell; novel; response; size; small molecule; trafficking; tumor; vascular bed

DESCRIPTION (provided by applicant): We have found that Akt signaling contributes to some of the more notable abnormalities in tumor vascular stroma. Those vascular abnormalities include the propensity for excessive vascular permeability leading to tissue edema and sluggish blood flow, extravasation of fibrin and other matrix proteins that alter the extracellular microenvironment, and the trafficking of inflammatory cells and tumor cells in and out of the tumor-associated vasculature. In addition, we also showed that rapamycin is an effective inhibitor of Akt signaling in the tumor stroma. This grant application is designed to study rapamycin's effects on the tumor stroma and to determine the impact of the anti-stromal effects of rapamycin on its anti-tumor efficacy. Both vascular and nonvascular stroma will be studied. Aim 1 is focused on identification of the vessel and vascular molecular targets that mediate rapamycin's anti-angiogenic efficacy. Aim 2 is designed to test the importance of rapamycin stromal targets in cancer inhibition. Aim 3 investigates rapamycin inhibition tumor cell trafficking across the endothelium and metastasis. PUBLIC HEALTH RELEVANCE: This project is designed to dissect the Akt pathway inhibitor, rapamycin, in the tumor microenvironment. Rapamycin is one the most specific small molecule inhibitors inc clinical use and inhibits mTOR with subsequent feedback onto upstream signaling that results from mTOR's function as an Akt kinase. While in clinical trials for cancer, recent data suggests that it functions more effectively when administered in a metronomic fashion, and our data suggests that it is an effective inhibitor of the tumor vasculature. This application proposes to dissect the stromal cellular targets of rapamycin in breast cancer, and investigate the overall impact of those targets on rapamycin's anti tumor efficacy.

描述（由申请人提供）：我们发现 Akt 信号传导导致肿瘤血管基质中一些更显着的异常。这些血管异常包括血管通透性过高导致组织水肿和血流缓慢、改变细胞外微环境的纤维蛋白和其他基质蛋白外渗，以及炎症细胞和肿瘤细胞进出肿瘤相关脉管系统。此外，我们还表明雷帕霉素是肿瘤基质中 Akt 信号传导的有效抑制剂。该拨款申请旨在研究雷帕霉素对肿瘤基质的影响，并确定雷帕霉素的抗基质效应对其抗肿瘤功效的影响。将研究血管和非血管基质。目标 1 的重点是鉴定介导雷帕霉素抗血管生成功效的血管和血管分子靶标。目标 2 旨在测试雷帕霉素基质靶标在癌症抑制中的重要性。目标 3 研究雷帕霉素抑制肿瘤细胞跨内皮运输和转移。公共健康相关性：该项目旨在剖析肿瘤微环境中的 Akt 通路抑制剂雷帕霉素。雷帕霉素是临床应用中最特异的小分子抑制剂之一，可抑制 mTOR，并随后反馈到 mTOR 作为 Akt 激酶的上游信号传导。在癌症临床试验中，最近的数据表明，以节拍方式给药时，它的功能更有效，而且我们的数据表明，它是肿瘤血管系统的有效抑制剂。本申请旨在剖析雷帕霉素在乳腺癌中的基质细胞靶点，并研究这些靶点对雷帕霉素抗肿瘤功效的总体影响。