Improving targeted therapy in FLT3-mutated AML

改善 FLT3 突变 AML 的靶向治疗

基本信息

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
项目类别：
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

项目摘要

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.

项目概要本申请描述了我对急性髓系白血病 (AML) 细胞信号转导的研究，该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个独立的人基于实验室的学术血液学/肿瘤学领域的医师科学家。在我的指导下宾夕法尼亚大学 (UPENN) 的主要研究导师 Martin Carroll 博士，我开发了一个结构化培训计划，包括密集的实验室研究、教学和由经验丰富的人员监督教师顾问委员会。拟议的研究将重点关注针对FLT3的耐药机制 AML 治疗基于 UPENN 进行的这些药物临床试验的重要见解。早期的由于靶点特异性较差且有限，新一代FLT3抑制剂（FLT3i）的热情不高。生物利用度。最近开发了新的药物，其针对 FLT3 的活性得到了改善，并且临床效果也有所改善。通过清除白血病母细胞来证明疗效。然而，这些药物并不能起到治疗作用，而且很多患者的反应是分化而不是根除白血病克隆。这引发了重要关于FLT3如何调节白血病细胞的分化状态的问题。在初步研究中，我确定 FLT3 抑制的下游新途径可导致组蛋白快速下调甲基转移酶，EZH2。 EZH2 是 PRC2 转录阻遏蛋白的催化成分。这项研究首次证明了 FLT3 对表观遗传修饰剂的调节作用。 EZH2 活性丧失与增加骨髓分化和降低致白血病性有关，使其成为一个有吸引力的研究目标作为 FLT3i 诱导分化的潜在机制。该提案旨在证明 PRC2 是 FLT3-ITD 白血病发生所必需的（目标 1），证明 FLT3i 功能性抑制 PRC2 活性（目标 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 信号传导的生物学并确定诱导终末期的改进方法 FLT3-ITD白血病细胞的分化。在进行拟议的学习和培训计划时，我将制定在转化研究领域建立独立职业所需的技能和专业知识。