The Role of PTEN and the PI3K Pathway in Prostate Cancer

描述（由申请人提供）：本计划项目资助的目标是阐明磷酸肌醇3-激酶（PI 3 K）通路在前列腺癌中的作用，并确定药物干预这种疾病的新靶点。在5年前构思该计划时，基于PTEN的丢失，证据正在出现，即PI 3 K通路参与人类前列腺癌。我们在阐明PI 3 K通路和产生模拟人类疾病的小鼠模型方面的进展导致了前列腺癌中PI 3 K信号传导的基本组分的鉴定，并提出了新的治疗方法和生物标志物。在下一个授权期提出的实验是这项工作的逻辑延伸，并把我们带到一些新的方向。最值得注意的是，我们将上一个资助期的项目1（Cantley）和项目2（Roberts）合并为一个项目（本提案的项目1），并增加了一名新的研究员Charles Sawyers博士作为新项目（项目3）的负责人。这三个项目中的每一个都专注于开发小鼠模型，这些模型可以以平行的方式进行分析，以确定PI 3 K信号通路的不同组分在前列腺癌中的重要性。项目1（Cantley和Roberts）阐述了前列腺肿瘤中PI 3 K的单个催化和调节亚基的重要性，这些亚基是由PTEN缺失引起的，并阐述了p110 a突变形式（由Sellers博士在人类前列腺肿瘤中发现）诱导小鼠前列腺瘤形成的能力。项目2（Sellers）的重点是使用基因表达谱来确定介导前列腺上皮内瘤变（PIN）的途径，在前列腺中表达活化AKT的小鼠中，并将这些谱与项目2和3中衍生的其他小鼠模型中观察到的谱以及人类肿瘤中的表达谱进行比较。项目3（Sawyers）解决了PI 3 K下游的途径，独立于AKT信号传导，有助于前列腺癌。Sawyers博士观察到，Jnk Ser/Thr激酶在缺乏PTEN的细胞中被激活，并且Jnk的缺失损害这些细胞的增殖。Sawyers博士将建立小鼠模型，以测试Jnk对由于PTEN缺失而形成前列腺肿瘤的重要性。小鼠转基因核心（DePinho）将产生三个项目所需的小鼠，病理学核心（Loda）和基因组学和生物信息学核心（Golub）将分析和比较三个项目中产生的肿瘤。一个行政核心（Cantley）将监督该计划的各个方面。

DESCRIPTION (provided by applicant): The goal of this Program Project Grant is to elucidate the role of the phosphoinositide 3-kinase (PI3K) pathway in prostate cancer and to identify new targets for pharmaceutical intervention in this disease. At that time that this program was conceived 5 years ago, evidence was emerging, based on loss of PTEN, that the PI3K pathway was involved in human prostate cancer. Our progress in elucidating the PI3K pathway and in generating mouse models that mimic human disease has led to the identification of essential components of PI3K signaling in prostate cancer and suggested new treatments and biomarkers. The experiments proposed in the next granting period are a logical extension of this work and take us in some new directions. Most notably, we have combined Project 1 (Cantley) and Project 2 (Roberts) from the previous funding period into a single project (Project 1 of this proposal) and have added a new investigator, Dr. Charles Sawyers, as leader of a new project (Project 3). Each of the three Projects focuses on developing mouse models that can be analyzed in a parallel fashion to determine the importance of distinct components of the PI3K signaling pathway in prostate cancer. Project 1 (Cantley and Roberts) addresses the importance of individual catalytic and regulatory subunits of PI3K in prostate tumors that result from loss of PTEN and addresses the ability of a mutant form of p110a (found in human prostate tumors by Dr. Sellers) to induce prostate neoplasia in mice. Project 2 (Sellers) focuses on using gene expression profiles to determine pathways that mediate prostate intraepithelial neoplasia (PIN) in mice expressing activated AKT in the prostate and in comparing these profiles to those observed in other mouse models derived in Projects 2 and 3 and to expression profiles in human tumors. Project 3 (Sawyers) addresses pathways downstream of PI3K, independent of AKT signaling, that contribute to prostate cancer. Dr. Sawyers has observed that the Jnk Ser/Thr kinase is activated in cells lacking PTEN and that deletion of Jnk impairs proliferation of these cells. Dr. Sawyers will generate mouse models to test the importance of Jnk for prostate tumor formation due to loss of PTEN. A Mouse Transgenic Core (DePinho) will generate the mice needed for the three projects and a Pathology Core (Loda) and Genomics and Bioinformatics Core (Golub) will analyze and compare the tumors generated in the three Projects. An Administrative Core (Cantley) will supervise all aspects of the program.