mTOR Signaling In Chronic Myelogenous Leukemia

慢性粒细胞白血病中的 mTOR 信号转导

• 批准号: 7405420
• 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
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-23 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405420
• 关键词: ABL1 gene; Apoptosis; Binding; Biochemical Genetics; Biogenesis; CCI-779; Candidate Disease Gene; Cells; Chimeric Proteins; Chromosomal translocation; Chronic; Chronic Myeloid Leukemia; Clinical; Dominant-Negative Mutation; Genes; Genetic Translation; Goals; Growth Factor; Imatinib; Imatinib mesylate; In complete remission; Interphase Cell; Laboratories; Lead; Malignant Neoplasms; Mediating; Messenger RNA; Mitotic Cell Cycle; Molecular; Myeloid Leukemia; Numbers; Nutrient; Pathogenesis; Pathway interactions; Patients; Phase I Clinical Trials; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Production; Protein Tyrosine Kinase; Proteins; Range; Rate; Recruitment Activity; Regulation; Reporting; Research Personnel; Resistance; Ribosomal Protein S6 Kinase; Ribosomes; Risk; 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; improved; inhibitor/antagonist; killings; leukemia; leukemogenesis; novel strategies; protein expression; response; ribosomal protein S6 kinase, 70kD, polypeptide 2

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）：该项目的远程目标是定义雷帕霉素（MTOR）哺乳动物靶标（MTOR）和mRNA翻译的机制，这有助于慢性髓性白血病（CML）的发病机理。 MTOR是细胞生长，增殖和凋亡的中心控制器，响应生长因子和养分的可用性。 MTOR效应子S6K和4E-BP1/EIF4E通过调节核糖体生物发生和cap依赖性翻译来介导这些作用。 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。为了检验这一假设，该研究者的实验室发现，BCR-ABL调节了几个MTOR效应子。 他们还确定了由CML细胞中MTOR和BCR-ABL调控的基因子集。 还发现对BCR-ABL和MTOR激酶的联合抑制作用协同作用以杀死CML细胞，并克服伊马替尼的耐药性。该提议有两个具体的目标。 AIM 1将检验以下假设：MTOR信号传导通过改变的翻译有助于BCR-ABL介导的白血病发生。 通过遗传和生化方法研究将研究受BCR-ABL翻译调节的EIF4E，S6K和特定基因的贡献。 AIM 2将确定雷帕霉素增强CML细胞杀死伊马替尼的机制。 这些研究将通过使用优势阴性突变体和siRNA的组合来干扰4E-BP1和S6K功能来完成。 这些研究可能导致靶向CML的新方法，以及其他以PI3K/AKT/MTOR轴失调为特征的癌症。 这些研究的临床相关性进一步强调了MTOR抑制剂CCI-779的I期临床试验与2004年秋季高危CML患者的I型抑制剂CCI-779的临床相关性。