mTOR Signaling In Chronic Myelogenous Leukemia

慢性粒细胞白血病中的 mTOR 信号转导

基本信息

批准号：
7648068
负责人：
HUNG Y. FAN
金额：
$ 22.85万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-23 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7648068
关键词：
ABL1 gene Apoptosis Binding Biochemical Biochemical Genetics Biogenesis CCI-779 Candidate Disease Gene Cells Chimeric Proteins Chromosomal translocation Chronic Myeloid Leukemia Clinical Dominant-Negative Mutation Genes Genetic Genetic Translation Goals Growth Factor Imatinib Imatinib mesylate In complete remission Interphase Cell Laboratories Lead Malignant Neoplasms Mediating Messenger RNA Mitotic Cell Cycle Molecular Nutrient Pathogenesis Pathway interactions Patients Phase I Clinical Trials Phosphatidylinositols Phosphorylation Phosphotransferases Production Protein Tyrosine Kinase Proteins Recruitment Activity Regulation Reporting Research Personnel Resistance Ribosomal Protein S6 Kinase Ribosomes Role Signal Pathway Signal Transduction Sirolimus Small Interfering RNA Structure Testing Translating Translations Ursidae Family c-abl Proto-Oncogenes cell growth clinically relevant cyclin D2 cyclin D3 falls high risk improved inhibitor/antagonist killings leukemia leukemogenesis mTOR protein novel strategies protein expression response ribosomal protein S6 kinase, 70kD, polypeptide 2

项目摘要

DESCRIPTION (provided by applicant): The long-range goal of this project is to define the mechanisms by which the mammalian target of rapamycin (mTOR) and mRNA translation contribute to the pathogenesis of chronic myelogenous leukemia (CML). mTOR is a central controller of cell growth, proliferation, and apoptosis in response to growth factors and the availability of nutrients. The mTOR effectors, S6K and 4E-BP1/eIF4E, mediate these effects by regulating ribosome biogenesis and cap-dependent translation. The central hypothesis guiding this application is that mTOR signaling contributes to cr-Abl-driven leukemogenesis. To test this hypothesis, this investigator's laboratory has found that several mTOR effectors are modulated by Bcr-Abl. They have also identified a subset of genes that are regulated by mTOR and Bcr-Abl in CML cells. Combined inhibition of the Bcr-Abl and mTOR kinases was also found to act synergistically to kill CML cells, and overcome imatinib-resistance. This proposal has two specific aims. Aim 1 will test the hypothesis that mTOR signaling contributes to Bcr-Abl-mediated leukemogenesis via altered translation. The contribution of eIF4E, S6K, and specific genes that are translationally regulated by Bcr-Abl will be investigated by using genetic and biochemical approaches. Aim 2 will determine the mechanisms by which rapamycin enhances imatinib-killing of CML cells. These studies will be accomplished by interfering with 4E-BP1 and S6K function, by using a combination of dominant negative mutants, as well as siRNA. These studies are likely to lead to novel approaches to target CML, as well as other cancers characterized by dysregulation of the PI3K/Akt/mTOR axis. The clinical relevance of these studies is further underlined by the planned opening of a Phase I clinical trial of the mTOR inhibitor, CCI-779, in combination with imatinib mesylate in patients with high-risk CML in the fall of 2004.

描述（由申请人提供）：该项目的长期目标是确定哺乳动物雷帕霉素靶标 (mTOR) 和 mRNA 翻译促进慢性粒细胞白血病 (CML) 发病机制的机制。 mTOR 是细胞生长、增殖和凋亡的中央控制器，响应生长因子和营养物质的可用性。 mTOR 效应子 S6K 和 4E-BP1/eIF4E 通过调节核糖体生物合成和帽依赖性翻译来介导这些效应。指导该应用的中心假设是 mTOR 信号传导有助于 cr-Abl 驱动的白血病发生。为了验证这一假设，本研究人员的实验室发现了多个 mTOR 效应器受 Bcr-Abl 调节。他们还鉴定了 CML 细胞中受 mTOR 和 Bcr-Abl 调节的基因子集。还发现 Bcr-Abl 和 mTOR 激酶的联合抑制可协同作用杀死 CML 细胞并克服伊马替尼耐药性。该提案有两个具体目标。目标 1 将检验 mTOR 信号传导通过改变翻译促进 Bcr-Abl 介导的白血病发生的假设。将使用遗传和生化方法研究 eIF4E、S6K 和 Bcr-Abl 翻译调节的特定基因的贡献。目标 2 将确定雷帕霉素增强伊马替尼对 CML 细胞的杀伤作用的机制。这些研究将通过使用显性失活突变体以及 siRNA 的组合来干扰 4E-BP1 和 S6K 功能来完成。这些研究可能会带来针对 CML 以及以 PI3K/Akt/mTOR 轴失调为特征的其他癌症的新方法。计划于 2004 年秋季启动 mTOR 抑制剂 CCI-779 与甲磺酸伊马替尼联合治疗高危 CML 患者的 I 期临床试验，进一步强调了这些研究的临床意义。