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。这些血管异常包括导致组织水肿和血流缓慢的过度血管渗透性倾向，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的血管系统。此外，我们还发现雷帕霉素是肿瘤基质中Akt信号传导的有效抑制剂。这项拨款申请旨在研究雷帕霉素对肿瘤基质的作用，并确定雷帕霉素的抗基质作用对其抗肿瘤功效的影响。血管和非血管间质都将被研究。目的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点。目的2旨在测试雷帕霉素基质靶点在肿瘤抑制中的重要性。目的3研究雷帕霉素对肿瘤细胞内皮转运和转移的抑制作用。公共卫生相关性：本项目旨在剖析肿瘤微环境中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，它抑制mTOR，随后反馈到上游信号，这是由mTOR作为Akt激酶的功能引起的。而在癌症的临床试验中，最近的数据表明，当以节拍方式给药时，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剂。本申请拟解剖雷帕霉素在乳腺癌中的基质细胞靶点，并探讨这些靶点对雷帕霉素抗肿瘤疗效的总体影响。

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.