The Role of AKT in Prostate Cancer

AKT 在前列腺癌中的作用

基本信息

批准号：
7683300
负责人：
WILLIAM R SELLERS
金额：
$ 31.89万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7683300
关键词：
AKT1 gene Ablation Advanced Malignant Neoplasm Aftercare Androgen Receptor Androgens Animals Biological Markers Cancer Patient Clinical Clinical Trials Collaborations Coupled Data Deoxyglucose Disease regression ETV1 gene Enzymes Frequencies Gene Targeting Genes Genomics Glucose Transporter Glycolysis Goals Grant Human Image Invasive Joints Lipids MAPK8 gene Malignant Neoplasms Malignant neoplasm of prostate Measurable Measurement Measures Metastatic Prostate Cancer Modeling Molecular Profiling Mus Mutant Strains Mice Mutation PTEN gene Pathologic Pathology Pathway interactions Pharmacodynamics Phenotype Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Plasma Positron-Emission Tomography Prostate Prostatic Intraepithelial Neoplasias Proto-Oncogene Proteins c-akt Publications Regulation Reporting Research Personnel Role SLC2A1 gene Sampling Signal Transduction Standards of Weights and Measures TMPRSS2 gene Testing Time Tissues Tracer Transcript Transcriptional Regulation Transgenic Organisms Up-Regulation Work Xenograft Model Xenograft procedure androgen independent prostate cancer base carcinogenesis design human FRAP1 protein inhibitor/antagonist kinase inhibitor mTOR Inhibitor mTOR inhibition men mouse model novel p27 Cell Cycle Protein p27 Enzyme Inhibitor pre-clinical programs response tumor uptake validation studies

AKT1 gene Ablation Advanced Malignant Neoplasm Aftercare Androgen Receptor Androgens Animals Biological Markers Cancer Patient Clinical Clinical Trials Collaborations Coupled Data Deoxyglucose Disease regression ETV1 gene Enzymes Frequencies Gene Targeting Genes Genomics Glucose Transporter Glycolysis Goals Grant Human Image Invasive Joints Lipids MAPK8 gene Malignant Neoplasms Malignant neoplasm of prostate Measurable Measurement Measures Metastatic Prostate Cancer Modeling Molecular Profiling Mus Mutant Strains Mice Mutation PTEN gene Pathologic Pathology Pathway interactions Pharmacodynamics Phenotype Phosphatidylinositols Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Plasma Positron-Emission Tomography Prostate Prostatic Intraepithelial Neoplasias Proto-Oncogene Proteins c-akt Publications Regulation Reporting Research Personnel Role SLC2A1 gene Sampling Signal Transduction Standards of Weights and Measures TMPRSS2 gene Testing Time Tissues Tracer Transcript Transcriptional Regulation Transgenic Organisms Up-Regulation Work Xenograft Model Xenograft procedure androgen independent prostate cancer base carcinogenesis design human FRAP1 protein inhibitor/antagonist kinase inhibitor mTOR Inhibitor mTOR inhibition men mouse model novel p27 Cell Cycle Protein p27 Enzyme Inhibitor pre-clinical programs response tumor uptake validation studies

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项目摘要

The PTEN/PISK/AKtpathway is a critical regulator of prostate carcinogenesis. Loss of the lipid phosphatase activity of PTEN and constitutive activation of phosphoinositide-3 kinase and Akt occur in high-grade and metastatic prostate cancers at high frequency. In the initial grant period we modeled the consequences of Akt activation in the murine prostate by developing a transgenicline (AKT1-Tg) where expressionof myristoylated, and hence activated human AKT1 is spatially restricted to the ventral prostate. These mice develop a highly penetrant prostatic intraepithelial neoplasia phenotype {Majumder, 2003 #1171}. We showed 1) that the phenotype is completely mTOR dependent {Majumder, 2004 #1170} 2) that the Hif1 D pathway is activated downstream of mTOR in this model and can acts as pharmacodynamic marker of mTOR activity; 3) that phosphorylation of eiF4G is a robust tissue marker of mTOR activity in mice and in humans {Majumder, 2004 #1170} (Tabernero et. al., in prep.); 4) that p27 acts as a phenotype checkpoint limiting progression to invasive cancer (Majumder et. al.,submitted), and 5) have confirmed the discovery of TMPRSS2:ERG translocation, and shown that this frequently co-occurs with PTEN deletion and that the endogenous TMPRSS2 transcript is regulated by mTOR signaling. Based on these data and other data illustrated in the preliminary data section we propose: Specific Aim 1: To validate pharmacodynamic signatures of mTOR activity in murine prostate models of PI3K pathway activation. To validate refined signatures of mTOR activity in clinical samples obtained in a clinical trial of RAD001 in prostate cancer patients. Specific Aim 2: To identifying a "response" signature in the AKT1-Tg model mouse. To cross-validate the response signature in murine models of PTEN loss and/or PI3K activation. To initiated validation studies in human plasma and prostate cancer samples. Specific Aim 3: To determine whether PI3K/AKT/mTOR pathway activation and TMPRSS2:ERG cooperate to induce transformation of the murine prostate.

PTEN/PISK/AKTPathway是前列腺癌发生的关键调节剂。脂质磷酸酶的损失 PTEN的活性和磷酸肌醇-3激酶和AKT的组成型激活发生在高级和高频转移前列腺癌。在最初的授予期内，我们对通过开发转基因线（Akt1-tg），在鼠前列腺中的Akt激活，其中表达肉豆蔻酰化，因此被激活的人Akt1在空间上仅限于腹侧前列腺。这些老鼠开发高度渗透的前列腺内肿瘤表型{Majumder，2003＃1171}。我们显示1）表型完全依赖于mtor {majumder，2004＃1170} 2）在该模型中，MTOR的下游途径被激活，并且可以充当药效标记 MTOR活动； 3）EIF4G的磷酸化是小鼠和在人类{Majumder，2004＃1170}（Tabernero et al。，in Prep。）; 4）P27充当表型检查点将进展为侵入性癌症（Majumder等人，提交），5）已确认发现 tmprss2：erg易位，并表明这种经常与pten删除同时发生，并且内源性TMPRSS2转录本受MTOR信号传导调节。基于这些数据和其他数据部分中所示的数据，我们建议：特定目的1：验证PI3K鼠前列腺模型中MTOR活性的药效学特征途径激活。验证在临床中获得的临床样本中MTOR活性的精致特征 RAD001在前列腺癌患者中的试验。特定目标2：在AKT1-TG模型鼠标中识别“响应”签名。交叉验证 PTEN损失和/或PI3K激活的鼠模型中的响应签名。开始验证研究人血浆和前列腺癌样品。特定目标3：确定PI3K/AKT/MTOR途径是否激活和TMPRSS2：ERG合作诱导鼠前列腺的转化。