Cellular Pharmacology of Rapamycin

描述(申请人提供)：雷帕霉素是一种临床批准的免疫抑制剂，在啮齿动物模型系统和临床癌症试验中都显示出显著的抗肿瘤活性。雷帕霉素的细胞活性反映了单个蛋白靶点的抑制作用，该靶点被称为雷帕霉素的哺乳动物靶点(MTOR)。这个大的(约290kD)的蛋白激酶是一个新的信号蛋白家族的成员，被称为磷脂酰肌醇(PI)3-激酶相关蛋白，它们共同在哺乳动物细胞的生长控制和基因组监测中发挥关键作用。越来越多的证据表明，通过PI3-激酶-AKT途径的信号失控与癌细胞对雷帕霉素的抗增殖作用的敏感性之间存在着强烈的联系。异常的PI3K信号是许多晚期侵袭性肿瘤的特征，包括胶质母细胞瘤、黑色素瘤、前列腺癌和乳腺癌。该项目的总体目标是确定mTOR在癌症中的信号功能，并进一步了解雷帕霉素对与癌症进展相关的mTOR依赖反应的影响。此外，我们打算详细探讨PI3-激酶-mTOR信号通路和低氧适应之间的相互作用，低氧适应是肿瘤发生的关键步骤。本提案的具体目的是：(1)比较雷帕霉素和基因诱导的mTOR缺乏对癌细胞增殖和致瘤活性的影响，(2)确定mTOR在低氧诱导的癌细胞HIF-1α积聚中的作用，以及(3)研究低氧诱导因子(HIF)-1抑制在雷帕霉素抗肿瘤活性中的作用。

DESCRIPTION (provided by applicant): Rapamycin is a clinically approved immunosuppressive agent that has displayed significant antitumor activities in both rodent model systems and clinical cancer trials. The cellular activities of rapamycin reflect the inhibition of a single protein target, termed the mammalian Target of Rapamycin (mTOR). This large (approximately 290 kD) protein kinase is a member of a novel family of signaling proteins termed phosphoinositide (PI) 3-kinase related kinases, which collectively play key roles in cell growth control and genome surveillance in mammalian cells. Accumulating evidence suggests a strong link between deregulated signaling through the PI 3-kinase - AKT pathway and the sensitivity of cancer cells to the anti-proliferative effects of rapamycin. Aberrant PI 3-kinase signaling is characteristic of many late-stage, aggressive tumors, including glioblastoma, melanoma, and cancers of the prostate and breast. The overall goals of this project are define the signaling functions of mTOR in cancers, and to further understand the impact of rapamycin on mTOR-dependent responses relevant to cancer progression. In addition, we intend to explore in detail the interplay between the PI 3-kinase -mTOR signaling pathway and hypoxic adaptation, a key step in tumorigenesis. The specific aims of the current proposal are: (1) to compare the effects of rapamycin versus genetically-induced mTOR deficiency on cancer cell proliferation and tumorigenic activity, (2) to define the roles of mTOR in hypoxia-induced HIF-1alpha accumulation in cancer cells, and (3) to examine the role of hypoxia-induced factor (HIF)-1 inhibition in the anticancer activity of rapamycin.