PI3K/PTEN/Akt signaling and the genesis of cancer

描述（由申请人提供）：丝氨酸/苏氨酸激酶Akt可能是人类癌症中最频繁活化的癌蛋白，其活化通常产生化学抗性，是癌症治疗的有吸引力的靶标。我们的长期目标是了解为什么Akt在人类癌症中经常被激活，并阐明Akt激活有助于癌症发生的机制，这是加强这种治疗的关键一步。我们正在使用遗传方法来评估Akt消融治疗癌症的可行性和生理后果。多年来，我们一直在描绘Akt在细胞和组织水平上的功能。通过采用小鼠Akt基因敲除，我们发现了Akt活性有助于细胞存活、细胞增殖和致癌转化易感性的几种机制。我们采用了几种小鼠模型，以表明Akt 1消融抑制这些模型中肿瘤的发展。目前，这项资助申请的主要目标是在细胞水平上，包括了解Akt在细胞增殖和肿瘤发生中的作用及其对mTORC 1的依赖性。在生物体水平上，我们将采用小鼠Akt基因的条件性缺失来确定对这些小鼠中发生的癌症的治疗效果。我们将验证并进一步了解Akt 1缺失与Akt 2缺失对癌症发生、进展和转移的影响。最后，我们将评估Akt下游效应子己糖激酶2的条件性缺失是否会影响肿瘤的发展，以及它是否可以作为癌症治疗的靶点。

DESCRIPTION (provided by applicant): The serine/theronine kinase Akt, perhaps the most frequently activated oncoprotein in human cancers, and whose activation often exerts chemoresistance, is an attractive target for cancer therapy. Our long-term goals are to understand why Akt is frequently activated in human cancers, and to elucidate the mechanisms by which Akt activation contributes to the genesis of cancer, a critical step toward enhancing such therapy. We are using genetic approaches to evaluate the feasibility and the physiological consequences of Akt ablation for cancer therapy. Over the years, we have been delineating the functions of Akt both at the cellular and organismal levels. By employing mouse knockouts of the Akt genes, we uncovered several mechanisms by which Akt activity contributes to cell survival, cell proliferation, and susceptibility to oncogenic transformation. We employed several mouse models to show that Akt1 ablation inhibits the development of neoplasia in these models. The current major objectives of this grant application, at the cellular level, include understanding the role of Akt in cell proliferation and tumorigenesis and its dependence on mTORC1. At the organismal level, we will employ conditional deletions of the Akt genes in the mouse to determine the therapeutic effect on cancer developed in these mice. We will verify and further understand the consequences of Akt1 deletion versus Akt2 deletion on cancer development, progression and metastasis. Finally, we will assess whether the conditional deletion of hexokinase 2, a downstream effector of Akt, could affect tumor development, and whether it could be targeted for cancer therapy.