Improving targeted therapy in FLT3-mutated AML

项目总结 这是我的导师临床科学家发展奖(K08-CA230190)的补充资料。K08-CA230190 于2020年7月1日获得资助，并详细介绍了促进我作为一名独立医生职业生涯的五年计划- 实验室血液学/肿瘤学领域的科学家。在我的初选指导下 宾夕法尼亚大学(UPenn)的研究导师马丁·卡罗尔博士，我开发了一种结构化的 培训计划，包括密集的实验室研究、教学和由经验丰富的教员监督 咨询委员会。拟议的研究集中在Flt3靶向治疗的意外反应 AML是基于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。早期一代Flt3 由于靶点特异性差和生物利用度有限，抑制剂(Flt3i)受到了不温不火的欢迎。 最近开发的新药物具有更好的抗Flt3活性和临床疗效，如 白血病原始细胞的清除就是证据。然而，这些药物并不能治愈，许多患者 应对措施是分化，而不是根除白血病克隆。这就提出了一些重要的问题 Flt3如何调节白血病细胞的分化状态。在初步研究中，我发现了一种新的途径 Flt3的下游抑制导致组蛋白甲基转移酶EZH2的快速下调。EZH2 是PRC2转录抑制因子的催化成分。这项研究是第一个论证 Flt3对表观遗传修饰物的调控。EZH2活性的丧失与髓系细胞增多有关 分化和降低白血病原性，使其成为潜在机制研究的一个有吸引力的目标 用于Flt3i诱导的分化。这项提议旨在证明PRC2对于FLT3-ITD是必要的 白血病发生(目标1)，证明Flt3i功能抑制PRC2活性(目标2)，并确定 抑制Flt3后EZH2下调的机制(目标3)。这些发现将为我们提供对 Flt3信号转导的生物学及诱导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 在翻译研究方面建立独立的职业生涯所必需的。我为我的第一个孩子的诞生而欣喜若狂 2019年11月22日的孩子；然而，这一关键的人生事件降低了我在年第1年之前和期间的工作效率 由于儿童保育需求，K08奖励期。本行政副刊将为 研究技术员加快了实验和项目的步伐，帮助我在 我的独立之路。

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.