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

基本信息

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
项目类别：
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

项目摘要

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）：慢性粒细胞白血病 (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 途径，驱动白血病细胞的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）是治疗早期 CML 患者的有效药物。然而，残留的 BCR-ABL+ 细胞在伊马替尼治疗后仍能存活，从而导致耐药突变的发生和疾病进展的恢复。为了更有效地杀死 BCR-ABL+ 细胞，从而实现 CML 的治愈性化疗，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来抑制细胞凋亡。尽管 Akt 信号转导活跃，但 Akt 诱导的糖酵解代谢的中断可阻止 Akt 依赖性细胞存活，从而恢复癌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清楚。该提案中的初步数据表明，Akt 通过下游蛋白激酶 S6K1 发出增加代谢和存活的信号。有趣的是，S6K1 也是 PI3K/Akt 通路上游元件的负调节因子，在负反馈环中发挥作用来调节 Akt 信号传导。因此，S6K1 具有致癌和肿瘤抑制活性，诱导 Akt 下游的生存代谢，同时通过负反馈抑制 Akt 信号传导。一种对抗 Akt 生存途径的新兴方法是通过灭活 S6K1 来干扰 Akt 诱导的代谢。本文提出的研究将探讨在测试 S6K1 在白血病中的致癌与肿瘤抑制功能的实验中灭活 S6K1 的治疗意义。具体来说，将使用 CML 小鼠模型中的 S6K1 缺陷小鼠来确定 S6K1 在 BCR-ABL 诱导的代谢和细胞凋亡抵抗中的作用。一组平行实验将评估 S6K1 缺陷对 Akt 白血病发生小鼠模型的影响，其中 Akt 通过诱导删除 Akt 上游调节因子 PTEN 直接激活。白血病小鼠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增强 CML 和其他激活 Akt 癌症的治疗效果提供机制和功能见解。公众健康关注慢性粒细胞白血病 (CML) 是一种血液癌症，约占成人白血病的 10%。目前首选的药物治疗甲磺酸伊马替尼可有效杀死大多数癌细胞，但其余细胞可能会产生耐药性并导致复发。该研究项目探索了一种新方法，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。这些实验的结果将带来新的策略来消除可能导致白血病复发的残留癌细胞。