Improving targeted therapy in FLT3-mutated AML

项目摘要 这是我的指导临床科学家发展奖（K 08-CA 230190）的补充。K08-CA230190 于2020年1月7日获得资助，并详细介绍了一个五年计划，以促进我作为一名独立医生的职业生涯- 实验室血液学/肿瘤学领域的科学家。在我的小学指导下 研究导师，马丁卡罗尔博士，在宾夕法尼亚大学（UPENN），我已经制定了一个结构化的 培训计划，包括密集的实验室研究，教学法，并由经验丰富的教师监督 咨询委员会。拟议的研究重点是对FLT 3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关键见解。前代FLT 3 由于靶点特异性差和生物利用度有限，FLT 3 i抑制剂受到了不冷不热的关注。 最近已经开发了具有改善的针对FLT 3的活性和临床功效的较新的药剂， 通过清除白血病母细胞来证明。然而，这些药剂不是治愈性的，许多患者 对白血病克隆的反应是分化而不是根除。这就提出了一些重要的问题， FLT 3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， FLT 3抑制的下游，导致组蛋白甲基转移酶EZH 2的快速下调。EZH2 是PRC 2转录抑制子的催化组分。这项研究首次证明了 FLT 3对表观遗传修饰的调控。EZH 2活性的丧失与髓样细胞增多有关。 分化和降低白血病发生，使其成为一个有吸引力的目标，研究作为一个潜在的机制 FLT 3 i诱导的分化。本提案旨在证明PRC 2对于FLT 3-ITD是必要的 白血病发生（Aim 1），证明FLT 3 i功能性抑制PRC 2活性（Aim 2），并确定 FLT 3抑制后EZH 2下调的机制（目的3）。这些发现将提供深入了解 FLT 3信号传导的生物学，并确定诱导FLT 3-ITD终末分化的改进方法 白血病细胞在进行拟议的研究和培训计划时，我将发展技能和专业知识， 在翻译研究中建立独立的职业生涯是必要的。我为我第一个孩子的出生而欣喜若狂 孩子在2019年11月22日出生;然而，这一关键的生活事件降低了我在2019年1月之前和期间的生产力。 K 08奖期间，由于儿童保育的要求。这笔行政补助金将为 研究技术员，以加快实验和项目的步伐，以帮助我继续前进， 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.