Improving targeted therapy in FLT3-mutated AML

改善 FLT3 突变 AML 的靶向治疗

• 批准号: 9892570
• 负责人: Pamela Jeannette Sung
• 金额: $ 19.47万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892570
• 关键词: Acute Myelocytic Leukemia; Advisory Committees; Apoptosis; Area; Biochemical; Biological Availability; Biology; Blast Cell; Blood Cells; Bone Marrow; CRISPR/Cas technology; Cell Line; Cell Proliferation; Cell Survival; ChIP-seq; Clinical; Clinical Trials; Complex; Cycloheximide; Data; Development Plans; Disease; Down-Regulation; Dysmyelopoietic Syndromes; Enhancers; Epigenetic Process; FDA approved; FLT3 gene; FLT3 inhibition; FLT3 inhibitor; Faculty; Flow Cytometry; Foundations; Generations; Genes; Genetic; Genetic Transcription; Goals; Half-Life; Hematology; Hematopoiesis; Hematopoietic Neoplasms; Histones; Homologous Gene; Human; In Vitro; Institution; JAK2 gene; Label; Laboratories; Laboratory Research; Leukemic Cell; Link; Lysine; MAP Kinase Gene; Maintenance; Malignant Neoplasms; Mentors; Mentorship; Methodology; Modeling; Mus; Mutate; Mutation; Myelogenous; Myeloproliferative disease; New Agents; Oncology; Pathway interactions; Patients; Pennsylvania; Pharmacology; Phosphotransferases; Physicians; Physiologic pulse; Polycomb; Post-Transcriptional Regulation; Proteasome Inhibition; Proteins; Proteome; Proteomics; RNA; Regulation; Research; Role; Sampling; Scientist; Signal Pathway; Signal Transduction; Specificity; Stat5 protein; Structure; Testing; Therapeutic; Training; Transcription Repressor; Translational Research; Undifferentiated; Universities; acute myeloid leukemia cell; base; career; career development; clinical efficacy; cytokine; epigenetic regulation; epigenome; experience; fetal liver kinase-2; functional genomics; gene repression; histone methyltransferase; histone modification; improved; in vivo; insight; leukemia; leukemogenesis; mouse model; mutant; novel; novel therapeutics; outcome forecast; overexpression; proto-oncogene protein pim; receptor; resistance mechanism; response; skills; stem; stem cells; targeted treatment; transcriptome sequencing

PROJECT SUMMARY This application describes my research on cell signaling in acute myeloid leukemia (AML) to be performed within the context of a 5-year mentored career development plan. My ultimate goal is to become an independent physician-scientist in the area of laboratory-based academic Hematology/Oncology. Under the guidance of my primary research mentor, Dr. Martin Carroll, at the University of Pennsylvania (UPENN), I have developed a structured training plan consisting of intensive laboratory research, didactics, and oversight by an experienced faculty advisory committee. The proposed research will focus on mechanisms of resistance to FLT3 targeted therapy in AML based on key insights from the clinical trials of these agents conducted at UPENN. Early generation FLT3 inhibitors (FLT3i) were met with lukewarm enthusiasm due to poor target specificity and limited bioavailability. Newer agents have recently been developed with improved activity against FLT3 and clinical efficacy as evidenced by clearance of leukemic blast cells. However, these agents are not curative and many patients respond with differentiation rather than eradication of the leukemic clone. This raises important questions about how FLT3 regulates the differentiation state of leukemia cells. In preliminary studies, I identified a novel pathway downstream of FLT3 inhibition that leads to rapid downregulation of the histone methyltransferase, EZH2. EZH2 is the catalytic component of the PRC2 transcriptional repressor. This research represents the first demonstration of FLT3 regulation of an epigenetic modifier. Loss of EZH2 activity has been linked to increased myeloid differentiation and decreased leukemogenicity, making it an attractive target to study as a potential mechanism for FLT3i-induced differentiation. This proposal aims to demonstrate that PRC2 is necessary for FLT3-ITD leukemogenesis (Aim 1), demonstrate that FLT3i functionally inhibit PRC2 activity (Aim 2), and determine the mechanism of EZH2 downregulation after FLT3 inhibition (Aim 3). These findings will provide insight into the biology of FLT3 signaling and identify improved approaches to induce terminal differentiation of FLT3-ITD leukemia cells. In undertaking the proposed studies and training plan, I will develop the skills and expertise necessary to establish an independent career in translational research.

项目总结 本申请描述了我对急性髓系白血病(AML)细胞信号的研究，将在 五年指导职业发展计划的背景。我的最终目标是成为一名独立的 内科医生-实验室血液学/肿瘤学领域的科学家。在我的指导下 宾夕法尼亚大学(UPenn)的主要研究导师马丁·卡罗尔博士，我已经开发出一种 有组织的培训计划，包括密集的实验室研究、教学和由经验丰富的 教职顾问委员会。拟议的研究将集中在针对Flt3的抗性机制上。 根据在宾夕法尼亚大学进行的这些药物的临床试验的关键见解，对急性髓细胞白血病的治疗。早些时候 新一代Flt3抑制剂(Flt3i)由于靶点特异性差和局限性而受到冷淡的欢迎。 生物利用度。最近开发的新药具有更好的抗Flt3和临床活性 清除白血病原始细胞所证明的疗效。然而，这些药物并不能治愈，而且许多 患者的反应是分化，而不是根除白血病克隆。这就提出了重要的 关于Flt3如何调节白血病细胞分化状态的问题。在初步研究中，我发现 Flt3抑制下游导致组蛋白快速下调的新途径 甲基转移酶，EZH2。EZH2是PRC2转录抑制因子的催化成分。这项研究 代表了Flt3对表观遗传修饰物的调节的第一个演示。EZH2活性的丧失一直是 与髓系分化增加和白血病原性降低有关，使其成为一个有吸引力的研究目标 作为Flt3i诱导分化的一种潜在机制。这项提议旨在证明PRC2是 Flt3-ITD白血病发生所必需的(Aim 1)，证明Flt3i功能抑制PRC2活性(Aim 2)，并确定Flt3抑制后EZH2下调的机制(目标3)。这些发现将 深入了解Flt3信号的生物学，并确定诱导末端的改进方法 Flt3-ITD白血病细胞的分化在承担拟议的学习和培训计划时，我将发展 在翻译研究领域建立独立事业所需的技能和专业知识。