The Role of PTEN and the PI3K Pathway in Prostate Cancer

描述(由申请者提供)：本计划项目资助的目标是阐明磷脂酰肌醇3-激酶(PI3K)途径在前列腺癌中的作用，并确定药物干预前列腺癌的新靶点。当时，这个计划是在5年前构思的，基于PTEN的缺失，有证据表明PI3K通路与人类前列腺癌有关。我们在阐明PI3K通路和建立模拟人类疾病的小鼠模型方面的进展导致了前列腺癌中PI3K信号的基本成分的识别，并提出了新的治疗方法和生物标志物。下一个授权期提出的实验是这项工作的合乎逻辑的延伸，并将我们带向一些新的方向。最值得注意的是，我们将前一个资助期的项目1(坎特利)和项目2(罗伯茨)合并为一个项目(本提案的项目1)，并增加了一名新的调查员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可以并行分析的小鼠模型，以确定PI3K信号通路的不同组成部分在前列腺癌中的重要性。项目1(坎特利和罗伯茨)阐述了PI3K的个别催化和调节亚基在由PTEN缺失引起的前列腺癌中的重要性，并探讨了突变形式的p110a(由Sellers博士在人类前列腺癌中发现)诱导小鼠前列腺癌的能力。项目2(Sellers)专注于使用基因表达谱来确定在前列腺表达激活的AKT的小鼠中介导前列腺上皮内瘤变(PIN)的途径，并将这些谱与在项目2和3中观察到的其他小鼠模型中观察到的以及与人类肿瘤中的表达谱进行比较。项目3(Sawyers)解决了PI3K下游的途径，独立于AKT信号，促进前列腺癌的发生。Sawyers博士观察到，在缺乏PTEN的细胞中，JNK Ser/Thr激酶被激活，JNK缺失会损害这些细胞的增殖。索耶斯博士将建立小鼠模型，以测试JNK在由于PTEN缺失而导致的前列腺癌形成中的重要性。一个小鼠转基因核心(DePinho)将产生三个项目所需的小鼠，一个病理学核心(Loda)和一个基因组和生物信息学核心(Golub)将分析和比较三个项目产生的肿瘤。行政核心(坎特利)将监督该计划的所有方面。

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.