Interrupting Akt-S6K1 metabolic control to enhance apoptotic responses in CML

中断 Akt-S6K1 代谢控制以增强 CML 中的细胞凋亡反应

• 批准号: 7686228
• 负责人: David R Plas
• 金额: $ 27万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7686228
• 关键词: 1-Phosphatidylinositol 3-Kinase; Accelerated Phase; Accounting; Age; Apoptosis; Apoptotic; Blast Phase; Blood Circulation; Blood Platelets; Bone Marrow; Cell Cycle Progression; Cell Death; Cell Survival; Cells; Cessation of life; Chromosomal translocation; Chromosomes, Human, Pair 9; Chronic Myeloid Leukemia; Chronic Phase; Chronic Phase of Disease; Clinical Treatment; Clinical Trials; Data; Development; Disease; Disease Progression; Disease remission; Drug resistance; Elements; Employee Strikes; Feedback; Gene Targeting; Gleevec; Glucose; Glycolysis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Human; Imatinib; Imatinib mesylate; Indium; Induction of Apoptosis; Interruption; Lead; Leukemic Cell; Life; Malignant Neoplasms; Mediating; Metabolic; Metabolic Control; Metabolism; Mus; Mutate; Mutation; Myelogenous; Neuraxis; Oncogenes; Oncogenic; PTEN gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Philadelphia Chromosome; Prostate; Protein Kinase; Protein Tyrosine Kinase; Proto-Oncogene Proteins c-akt; Public Health; Reciprocal Translocation; Regulation; Relapse; Research; Research Project Grants; Research Proposals; Residual Cancers; Residual state; Resistance; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Sirolimus; Staging; Stem cells; TP53 gene; Testing; Therapeutic; Treatment Efficacy; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; adult leukemia; base; bcr-abl Fusion Proteins; cancer cell; cancer type; cell killing; chemotherapy; cytokine; design; effective therapy; granulocyte; insight; killings; leukemia; leukemogenesis; malignant breast neoplasm; mouse model; novel strategies; prevent; programs; research study; response; small hairpin RNA; tumorigenesis

DESCRIPTION (provided by applicant): Chronic Myelogenous Leukemia (CML) is a hematopoietic stem cell disorder triggered by expression of the BCR-ABL oncogene from the t(9;22) chromosomal translocation (the Philadelphia Chromosome). BCR- ABL drives apoptosis resistance and cytokine-independent proliferation in leukemic cells by activating the phosphatidylinositol 3'-kinase (PI3K)/Akt pathway. The tyrosine kinase inhibitor imatinib (Gleevec) is an effective treatment for CML patients in early stages of the disease. However, residual BCR-ABL+ cells survive imatinib treatment, permitting the development of drug-resistant mutations and resumption of disease progression. To achieve more efficient killing of BCR-ABL+ cells and, thus, curative chemotherapy in CML, new strategies to augment imatinib-induced apoptosis are required. Akt represses apoptosis by activating cellular glycolysis. Interruptions in Akt-induced glycolytic metabolism prevent Akt-dependent cell survival, restoring homeostatic control of apoptosis in cancer cells despite active Akt signal transduction. The signaling pathway that coordinates Akt metabolic and survival signals is poorly defined. Preliminary data in this proposal show that Akt signals increased metabolism and survival through the downstream protein kinase S6K1. Interestingly, S6K1 is also a negative regulator of upstream elements in the PI3K/Akt pathway, acting in a negative feedback loop to modulate Akt signaling. Thus S6K1 has both oncogenic and tumor suppressor activities, inducing survival metabolism downstream of Akt while simultaneously suppressing Akt signaling through negative feedback. An emerging approach for counteracting the Akt survival pathway is based on interfering with Akt- induced metabolism by inactivating S6K1. Research proposed here will explore the therapeutic implications of inactivating S6K1 in experiments that test the oncogenic vs. tumor suppressor functions of S6K1 in leukemia. Specifically, the role of S6K1 in BCR-ABL-induced metabolism and apoptosis resistance will be determined using S6K1-deficient mice in a mouse model of CML. A parallel set of experiments will assess the effects of S6K1-deficiency in a mouse model of Akt leukemogenesis where Akt is directly activated through the inducible deletion of PTEN, an upstream regulator of Akt. Results from mouse models of leukemia will then be used to design and test novel approaches for enhancing apoptotic responses in leukemic cells by interfering with the Akt metabolic program. The results of our experiments will provide mechanistic and functional insights for enhancing therapeutic efficacy in CML and other cancers with activated Akt. PUBLIC HEALTH REVANCE Chronic Myelogenous Leukemia (CML) is a cancer of the blood that accounts for approximately 10% of adult leukemia. The currently preferred drug treatment, imatinib mesylate, effectively kills most cancer cells, but the remaining cells can acquire drug-resistance and cause relapse. This research project explores a new approach to augment the cell-killing ability of the current treatment by specifically interfering with cancer-cell metabolism. Results of these experiments will lead to novel strategies for eliminating the residual cancer cells that can cause relapse in leukemia.

描述（由申请人提供）：慢性髓性白血病（CML）是一种造血干细胞疾病，由t（9;22）染色体易位（费城染色体）的BCR-ABL癌基因表达引发。BCR- ABL通过激活磷脂酰肌醇3’-激酶(PI3K)/Akt通路，促进白血病细胞凋亡抵抗和细胞因子非依赖性增殖。酪氨酸激酶抑制剂伊马替尼（格列卫）是CML早期患者的有效治疗方法。然而，残留的BCR-ABL+细胞在伊马替尼治疗后存活，允许耐药突变的发展和疾病进展的恢复。为了更有效地杀死BCR-ABL+细胞，从而治疗CML的化疗，需要新的策略来增强伊马替尼诱导的细胞凋亡。Akt通过激活细胞糖酵解抑制细胞凋亡。Akt诱导的糖酵解代谢中断阻止Akt依赖的细胞存活，尽管Akt信号转导活跃，但在癌细胞中恢复细胞凋亡的稳态控制。协调Akt代谢和生存信号的信号通路尚不明确。本研究的初步数据表明，Akt信号通过下游蛋白激酶S6K1增加代谢和存活。有趣的是，S6K1也是PI3K/Akt通路上游元件的负调控因子，通过负反馈回路调节Akt信号。因此，S6K1同时具有致癌和抑瘤活性，诱导Akt下游的生存代谢，同时通过负反馈抑制Akt信号传导。一种新兴的对抗Akt存活通路的方法是通过使S6K1失活来干扰Akt诱导的代谢。本文提出的研究将探索灭活S6K1的治疗意义，在实验中测试S6K1在白血病中的致癌和肿瘤抑制功能。具体来说，S6K1在bcr - abl诱导的代谢和细胞凋亡抵抗中的作用将在CML小鼠模型中通过S6K1缺陷小鼠来确定。一组平行的实验将评估s6k1缺乏症对Akt白血病小鼠模型的影响，其中Akt通过诱导PTEN （Akt的上游调节因子）的缺失直接被激活。小鼠白血病模型的结果将用于设计和测试通过干扰Akt代谢程序来增强白血病细胞凋亡反应的新方法。我们的实验结果将为提高活化Akt治疗CML和其他癌症的疗效提供机制和功能见解。慢性髓性白血病（CML）是一种血液癌症，约占成人白血病的10%。目前首选的治疗药物甲磺酸伊马替尼可以有效杀死大多数癌细胞，但剩余的细胞可能获得耐药性并导致复发。本研究项目探索了一种新的方法，通过特异性干扰癌细胞代谢来增强当前治疗的细胞杀伤能力。这些实验的结果将导致新的策略消除残留的癌细胞，可以导致白血病复发。