Pathologic Signaling Pathways in AML Cells

AML 细胞的病理信号通路

• 批准号: 10341044
• 负责人: MARTIN CARROLL
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10341044
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute Myelocytic Leukemia; Affect; American; Binding; Biochemical Pathway; Biological Assay; Cell Count; Cell Cycle Regulation; Cell Line; Cell Proliferation; Cell Survival; Clinical; Clinical Trials; Complex; Cytarabine; DNA; Data; Disease; Drug Combinations; Equilibrium; Etoposide; FLT3 gene; FLT3 inhibitor; FOXO3A gene; FRAP1 gene; Generations; Growth Factor; Hematopoietic Neoplasms; Human; IL3 Gene; In Vitro; Individual; Inositol; Laboratories; Lead; Leukemic Cell; Life; Metabolic; Methodology; Methods; Modeling; Mus; Mutate; Pathogenesis; Pathologic; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Pre-Clinical Model; Process; Proteins; Proto-Oncogene Proteins c-akt; Raptors; Regulation; Relapse; Reporting; Research Design; Research Proposals; Sampling; Series; Signal Pathway; Signal Transduction; Sirolimus; Therapeutic; Transcriptional Regulation; Translations; United States; United States National Institutes of Health; Veterans; Work; Xenograft procedure; acute myeloid leukemia cell; c-myc Genes; cancer cell; cell growth; cell transformation; chemosensitizing agent; chemotherapy; chromatin immunoprecipitation; combinatorial; cytotoxic; improved; in vivo; inhibitor; insulin signaling; leukemic stem cell; molecular subtypes; novel strategies; novel therapeutics; promoter; small molecule inhibitor; success

Abstract: Acute myeloid leukemia (AML) is a serious blood cancer that affects United States Veterans and other individuals. Multiple studies have demonstrated that active signaling pathways are a necessary step to leukemic cell transformation. However, the mechanism(s) of activated signaling in FLT3 wild type AML are poorly described. We hypothesize that constitutive activation of the PI3 kinase pathway leads to activation of a complex called mammalian target of rapamycin 2 (mTORC2) which regulates diverse pathways to balance cell growth and survival in AML cells. In this proposal, we will define these signaling pathways and determine if inhibition of mTORC2 alone or in combination with other drugs will enhance survival in pre-clinical models of AML leading to new therapies for this challenging disease. 1. Objective(s): The overall objective of the research proposal is to define the mechanisms of activated cell signaling in AML cells, determine the biochemical pathways regulated by mTORC2 in AML cells and determine if inhibition of mTORC2 in pre-clinical models can increase survival of individuals with AML. 2. Research Design: We propose three Specific Aims. Specific Aim 1) Confirm that 4EBP1 is a target of MTORC2 and not MTORC1 in human AML samples and define whether MTORC2 regulates cell survival or cell growth. Specific Aim 2) Determine if mTORC2 Regulates FOXO 3 phosphorylation in AML cells to Regulate Cell Survival. Specific Aim 3) Determine if combinatorial MTORC1/MTORC2 inhibition in combination with chemotherapy or Bcl2 inhibition suppresses AML cell growth in pre- clinical models. 3. Methodology: Specific Aim 1 will primary use human AML cells and primary human AML cells in culture. Specific Aim 2 will use similar methods but also assess FOXO binding to DNA using chromatin immunoprecipitation. Specific Aim 3 will focus on studies in a xenotransplantation model of AML developed by our laboratory. 4. Findings: We anticipate confirming that mTORC2 is actually a master regulator of signaling in AML cells. In particular, we anticipate that mTORC2 regulates 4EBP1 to regulate protein translation. We also anticipate that mTORC2 regulates FOXO proteins to regulate c-Myc expression. Finally, we anticipate that mTORC2 inhibition will work alone or in combination with other therapies to inhibit AML cell survival in vivo. 5. Clinical Relationships: These studies will use primary material from patients with AML and will be used to develop a new approach to therapy of the disease.

摘要：急性髓样白血病（AML）是一种影响联合的严重血液癌 州退伍军人和其他个人。多项研究表明活跃 信号通路是白血病细胞转化的必要步骤。但是， FLT3野生型AML中活化信号传导的机理描述很差。我们 假设PI3激酶途径的本构激活导致A激活 复合物称为雷帕霉素2（MTORC2）的哺乳动物靶 平衡细胞生长和AML细胞存活的途径。在此提案中，我们将 定义这些信号通路，并确定单独抑制MTORC2还是在 与其他药物的结合将在AML的临床前模型中提高生存率 导致这种具有挑战性的疾病的新疗法。 1。目标：研究建议的总体目标是定义 AML细胞中活化细胞信号的机制，确定生化 由MTORC2在AML细胞中调节的途径，并确定MTORC2的抑制是否抑制 在临床前模型可以增加AML个体的存活。 2。研究设计：我们提出了三个具体目标。具体目标1）确认 4EBP1是MTORC2的靶标，而不是人类AML样品中的MTORC1并定义 MTORC2是否调节细胞存活或细胞生长。特定目标2）确定是否 MTORC2调节AML细胞中FOXO 3磷酸化以调节细胞存活。 特定目标3）确定组合MTORC1/mTORC2是否抑制 与化学疗法或BCL2抑制结合抑制AML细胞的生长 临床模型。 3。方法论：特定目标1将主要使用人类AML细胞和主要的AML细胞 人类AML培养中的细胞。特定目标2将使用类似的方法，但也会评估 FOXO使用染色质免疫沉淀与DNA结合。具体目标3将集中 关于我们实验室开发的AML的异种移植模型的研究。 4。调查结果：我们预计MTORC2实际上是 AML细胞中的信号传导。特别是，我们预计MTORC2将4EBP1调节为 调节蛋白质翻译。我们还预计MTORC2会调节Foxo蛋白 调节C-MYC表达。最后，我们预计MTORC2抑制作用将起作用 单独或与其他疗法抑制体内AML细胞存活。 5。临床关系：这些研究将使用患者的主要材料 AML并将用于开发一种疾病治疗的新方法。