AKT pathway as a therapeutic tumor vessel target

描述(由申请人提供)：我们发现Akt信号与肿瘤血管间质中一些更显著的异常有关。这些血管异常包括血管通透性过高导致组织水肿和血流迟缓，纤维蛋白和其他基质蛋白渗出改变细胞外微环境，以及炎细胞和肿瘤细胞进出肿瘤相关血管系统。此外，我们还发现雷帕霉素是肿瘤间质中Akt信号的有效抑制剂。这项拨款申请旨在研究雷帕霉素对肿瘤间质的影响，并确定雷帕霉素的抗间质作用对其抗肿瘤效果的影响。我们将对血管和非血管基质进行研究。目的1着重于鉴定介导雷帕霉素抗血管生成作用的血管和血管分子靶点。目的2旨在测试雷帕霉素基质靶点在癌症抑制中的重要性。目的3研究雷帕霉素抑制肿瘤细胞跨血管内皮细胞的迁移和转移。公共卫生相关性：该项目旨在剖析肿瘤微环境中Akt途径抑制剂雷帕霉素。雷帕霉素是INC临床使用的最特异的小分子抑制剂之一，它抑制mTOR，随后反馈到mTOR的上游信号，导致mTOR作为Akt激酶的功能。而在癌症的临床试验中，最近的数据表明，当以节律方式给药时，它的功能更有效，我们的数据表明，它是一种有效的肿瘤血管抑制物。这项申请建议剖析乳腺癌中雷帕霉素的间质细胞靶点，并调查这些靶点对雷帕霉素抗肿瘤疗效的整体影响。

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.