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：
10277509
负责人：
Pamela Jeannette Sung
金额：
$ 5.4万
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 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10277509
关键词：
Acute Myelocytic Leukemia Administrative Supplement Advisory Committees Apoptosis Area Award Biochemical Biological Availability Biology Birth Blast Cell Blood Cells Bone Marrow CRISPR/Cas technology Cell Line Cell Proliferation Cell Survival ChIP-seq Child Clinical Clinical Trials Complex Cycloheximide Data Disease Down-Regulation Dysmyelopoietic Syndromes Enhancers Epigenetic Process Event FDA approved FLT3 gene FLT3 inhibition FLT3 inhibitor Faculty Five-Year Plans Flow Cytometry Foundations Funding 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 Life Link Lysine MAP Kinase Gene Maintenance Malignant Neoplasms Mentored Clinical Scientist Development Award (K08)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 Productivity Prognosis 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 clinical efficacy cytokine epigenetic regulation epigenome experience experimental study fetal liver kinase-2 functional genomics gene repression histone methyltransferase histone modification improved in vivo insight leukemia leukemogenesis mouse model mutant novel novel therapeutics overexpression parent grant proto-oncogene protein pim receptor response skills stem stem cells targeted treatment transcriptome sequencing

项目摘要

PROJECT SUMMARY This is a Supplement for my Mentored Clinical Scientist Development Award (K08-CA230190). K08-CA230190 was funded on 07/01/2020 and details a five-year plan to promote my career as 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 focuses on unanticipated responses 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. I am overjoyed with the birth of my first child on 11/22/2019; however, this critical life event has reduced my productivity prior to and during Year 1 of the K08 award period due to childcare demands. This administrative supplement will provide funding for a research technician to accelerate the pace of experiments and projects to help me continue to move forward in my path to independence.

项目概要这是我的指导临床科学家发展奖 (K08-CA230190) 的补充。 K08-CA230190 于 2020 年 7 月 1 日获得资助，详细介绍了促进我作为独立医生职业生涯的五年计划 - 基于实验室的学术血液学/肿瘤学领域的科学家。在我小学老师的指导下宾夕法尼亚大学 (UPENN) 的研究导师 Martin Carroll 博士，我开发了一个结构化的培训计划包括密集的实验室研究、教学和经验丰富的教师的监督咨询委员会。拟议的研究重点是 FLT3 靶向治疗的意外反应 AML 基于在 UPENN 进行的这些药物临床试验的重要见解。早期 FLT3 由于靶标特异性差和生物利用度有限，抑制剂（FLT3i）的热情不高。最近开发了新的药物，其抗 FLT3 的活性和临床疗效均得到改善，如下所示：白血病母细胞的清除证明了这一点。然而，这些药物并不能治愈，许多患者通过分化而不是根除白血病克隆来做出反应。这提出了重要的问题 FLT3如何调节白血病细胞的分化状态。在初步研究中，我发现了一条新途径 FLT3 抑制的下游，导致组蛋白甲基转移酶 EZH2 快速下调。 EZH2 是 PRC2 转录抑制子的催化成分。这项研究代表了首次论证 FLT3 对表观遗传修饰因子的调节。 EZH2 活性丧失与骨髓细胞增多有关分化和降低致白血病性，使其成为潜在机制研究的有吸引力的目标用于FLT3i诱导的分化。该提案旨在证明 PRC2 对于 FLT3-ITD 是必要的白血病发生（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）。这些发现将提供深入了解 FLT3 信号传导的生物学并确定诱导 FLT3-ITD 终末分化的改进方法白血病细胞。在进行拟议的学习和培训计划时，我将发展技能和专业知识在转化研究中建立独立的职业生涯是必要的。我对我的第一个孩子的诞生感到非常高兴 2019 年 11 月 22 日儿童；然而，这一重大的生活事件降低了我在第一年之前和期间的生产力由于育儿需求，K08奖励期。该行政补充将为研究技术员加快实验和项目的步伐，帮助我继续前进我的独立之路。