PI3K/PTEN/Akt signaling and the genesis of cancer

描述(申请人提供)：丝氨酸/丝氨酸激酶Akt，可能是人类癌症中最频繁激活的癌蛋白，其激活通常会产生化疗耐药，是癌症治疗的一个有吸引力的靶点。我们的长期目标是了解Akt在人类癌症中频繁激活的原因，并阐明Akt激活促进癌症发生的机制，这是加强此类治疗的关键一步。我们正在使用遗传学方法来评估Akt消融治疗癌症的可行性和生理后果。多年来，我们一直在描述Akt在细胞和组织水平上的功能。通过利用小鼠敲除Akt基因，我们揭示了Akt活性有助于细胞存活、细胞增殖和对致癌转化的敏感性的几个机制。我们采用了几种小鼠模型来证明Akt1消融可以抑制这些模型中肿瘤的发展。目前，在细胞水平上，这项资助申请的主要目标包括了解Akt在细胞增殖和肿瘤发生中的作用及其对mTORC1的依赖。在生物体水平上，我们将采用有条件地删除小鼠中的Akt基因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Akt1缺失和Akt2缺失对癌症发生、进展和转移的影响。最后，我们将评估Akt下游效应蛋白己糖激酶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。 公共卫生相关性：丝氨酸/丝氨酸激酶Akt可能是人类癌症中最频繁激活的癌蛋白，其激活通常会产生化疗耐药，是癌症治疗的一个有吸引力的靶点。为了靶向Akt在癌症中的激活，重要的是要了解为什么它在癌细胞中经常被激活，以及Akt的关键下游效应因子是什么。我们的最终目标是确定癌症发生所需的Akt最关键的下游效应因子，并将其用于癌症治疗。为此，我们采用了细胞水平的体外研究和生物水平的体内研究。

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. PUBLIC HEALTH RELEVANCE: 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. In order to target Akt activation in cancer, it is important to understand why it is frequently activated in cancer cells, and what are the critical downstream effectors of Akt. Our ultimate goal is identify the most critical downstream effectors of Akt required for the genesis of cancer, and to target them for cancer therapy. For these purpose we are employing both in vitro studies at the cellular level and in vivo studies at the organismal level.