The role of Phosphoinositide 3 Kinase isoforms in Prostate Cancer

磷酸肌醇 3 激酶亚型在前列腺癌中的作用

• 批准号: 8299646
• 负责人: LEWIS C. CANTLEY
• 金额: $ 45.48万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8299646
• 关键词: 1-Phosphatidylinositol 3-Kinase; AKT inhibition; Acute; Adaptor Signaling Protein; Address; Affect; Aftercare; Alleles; Androgen Receptor; Antibodies; Automobile Driving; Binding; Biological Markers; Biopsy; Breeding; CCI-779; Cancer Model; Cancer Patient; Cancer cell line; Cell Death; Cell Line; Cell Survival; Cells; Chin; Clinical Trials; Co-Immunoprecipitations; Collaborations; Colon Carcinoma; Complex; Development; Disease; Dominant-Negative Mutation; Drug Delivery Systems; Drug Monitoring; Dysplasia; EGF gene; Embryo; Enzymes; Epidermal Growth Factor Receptor; Epithelial; Event; Family; Fibroblasts; Gene Components; Gene Deletion; Gene Expression; Gene Expression Profile; Genes; Genetic; Grant; Growth; Growth Factor; HRAS gene; Histology; Human; Immunohistochemistry; Individual; Insulin-Like Growth Factor I; Intestinal Polyps; Intraepithelial Neoplasia; Japanese Population; Knock-in Mouse; Laboratories; Life; Lipids; Luciferases; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Malignant neoplasm of prostate; Mass Spectrum Analysis; Mediating; Messenger RNA; Modeling; Molecular Profiling; Molecular Weight; Monophenol Monooxygenase; Mus; Mutation; Neoplasms; Oncogenic; PC3 cell line; PDGFRB gene; PIK3CA gene; PTEN gene; Pathology; Pathway interactions; Penetrance; Pharmaceutical Preparations; Phosphatidylinositols; Phosphoinositide Pathway; Phosphoric Monoester Hydrolases; Phosphotransferases; Platelet-Derived Growth Factor; Play; Principal Investigator; Progress Reports; Prostate; Prostatic Neoplasms; Protein Isoforms; Proteins; Proto-Oncogene Proteins c-akt; Puberty; Regulator Genes; Relative (related person); Research Personnel; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Solid Neoplasm; Testing; Therapeutic Intervention; Tissues; Transgenes; Transgenic Mice; Tumor Cell Line; Tumor Suppressor Genes; Tumor-Derived; Tumorigenicity; Western Blotting; Work; advanced disease; base; cancer type; cell growth; cell transformation; in vivo; indexing; inhibitor/antagonist; interest; killings; kinase inhibitor; knock-down; mTOR Inhibitor; malignant breast neoplasm; member; men; mouse model; mutant; neoplastic cell; novel; prevent; probasin; programs; promoter; receptor; research study; response; tumor; tumorigenesis; tumorigenic; upstream kinase

The phosphoinositide 3-kinase (PI3K) signaling pathway has been highly implicated in human prostate cancer on the basis of frequent loss of the tumor suppressor gene, PTEN in advanced disease. PTEN encodes a phosphatase that hydrolyzes the lipid product of PI3K, phosphatidylinositol-3,4,5-trisphosphate and loss of PTEN results in hyperactivation of the protein-Ser/Thr kinase AKT as well as other effectors of the PI3K pathway. In this project, we propose to further elucidate components of the PI3K pathway that contribute to prostate cancer. In addition, we propose to manipulate endogenous PI3K and PTEN genes and introduce oncogenic mutations of PI3K into mice in order to test the necessity and sufficiency of PI3K isoforms for development of prostate cancer. This project has three specific aims. Aim 1: We will attempt to identify upstream activators of PI3K in human prostate cancer cell lines and in xenograph models by immunoprecipitating PI3K and identifying co-precipitating proteins. The results of this study should reveal protein-Tyr kinase activators of PI3K that contribute to prostate cancer and that could be targeted for therapeutic intervention. Aim 2: We will introduce oncogenic mutants of the p110a subunit of PI3K into prostate epithelial tissue by transgene and knockin approaches and determine the effect of these mutations on prostate neoplasia and on gene expression profiles. The results of this study will be compared to our previous results with PTEN deletions and with results from mouse models being developed in the Sellers' laboratory (Project 2) and Sawyers' laboratory (Project 3) where activated genes for components downstream of the PI3K pathway are being introduced into the prostate. Aim 3: We will introduce a drug- inducible dominant negative form of PI3K to determine the effect of acute inhibition of this pathway on prostate tumors that develop due to loss of PTEN. In addition, we will delete specific genes for catalytic and regulatory subunits of class IA PI3K family in the prostate in the context of prostate-specific PTEN deletion in order to determine which isoforms of PI3K are critical for tumor formation. The results of this study will predict whether drugs that target specific PI3K isoforms will be effective in treating this disease.

磷酸肌醇3-激酶（PI3K）信号传导途径已高度与人类前列腺有关 癌症是基于经常损失肿瘤抑制基因，即晚期疾病中的PTEN。 PTEN 编码一种水解PI3K，磷脂酰肌醇-3,4,5-三磷酸的脂质产物的磷酸酶 PTEN的丧失导致蛋白质酶/THR激酶AKT以及其他效应子的过度激活 PI3K途径。在这个项目中，我们建议进一步阐明PI3K途径的组件 有助于前列腺癌。此外，我们建议操纵内源性PI3K和PTEN基因 并将PI3K的致癌突变引入小鼠中，以测试PI3K的必要性和充分性 前列腺癌发展的同工型。该项目具有三个特定的目标。目标1：我们将尝试 通过 免疫沉淀PI3K并鉴定共沉淀的蛋白质。这项研究的结果应揭示 PI3K的蛋白质-TYR激酶激活剂，有助于前列腺癌，可以针对目标 治疗干预。 AIM 2：我们将在P110a PI3K的P110a亚基中引入pi3k的致癌突变体 前列腺上皮组织通过转基因和敲除方法，并确定这些突变的作用 在前列腺肿瘤和基因表达谱上。这项研究的结果将与我们的 PTEN删除的先前结果以及卖方中鼠标模型的结果 实验室（项目2）和锯生实验室（项目3），其中激活了组件的基因 PI3K途径的下游正在引入前列腺。目标3：我们将引入药物 - PI3K的诱导主要负面形式，以确定该途径急性抑制的影响 由于PTEN损失而出现的前列腺肿瘤。另外，我们将删除用于催化和的特定基因 在前列腺特异性pten删除的背景下，IA级PI3K家族的监管亚基 为了确定哪种PI3K同工型对于肿瘤形成至关重要。这项研究的结果将 预测靶向特定PI3K同工型的药物是否有效治疗该疾病。