FLT3 Tyrosine Kinase Inhibitors As Therapy for Leukemia

FLT3 酪氨酸激酶抑制剂治疗白血病

• 批准号: 6485142
• 负责人: DONALD SMALL
• 金额: $ 29.1万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6485142
• 关键词: NOD mouse; SCID mouse; acute myelogenous leukemia; antineoplastics; cell line; drug discovery /isolation; enzyme inhibitors; growth factor receptors; human tissue; patient oriented research; protein structure function; protein tyrosine kinase; protooncogene; tissue /cell culture

DESCRIPTION (provided by applicant): Our long-term goals are to increase the cure rate and decrease chemotherapy-related toxicity for patients with leukemia. In particular, we are interested in patients whose leukemias express an activated FLT3 receptor, either as a result of mutation or ligand co-expression. The 20-40 percent of AML patients with mutations of the FLT3 receptor have particularly poor prognoses, with cures in the 10-20 percent range for pediatric and adult populations. This contrasts with cure rates of 40-50 percent for AML patients without mutant FLT3. This makes the development of novel strategies for these patients imperative if we are to effect improvements in their outcome. The most common form of mutations in the FLT3 receptor consists of small (18-112 bp) internal tandem duplications (lTDs) which are unique for each patient but all map to the juxtamembrane region, and point mutations affecting aspartic acid 835 in the kinase domain. Both of these mutations constitutively activate the tyrosine kinase domain of the FLT3 receptor which is required for signaling and transformation. By screening >10,000 small molecules from a library of tyrosine kinase inhibitors in a cell-based assay, we have identified several compounds that are able to completely inhibit FLT3 signaling with IC5Os in the single digit nM range. We propose to study the mechanisms by which FLT3 is constitutively activated and study how the FLT3 inhibitors interfere with these mechanisms. Responses of primary leukemic cells and cell lines to treatment with FLT3 inhibitors will be studied and the possible synergistic killing of cells when combined with chemotherapies will be explored. Signal transduction will be studied in cell lines and, in a more limited fashion, in primary cells in order to establish correlations of changes in signaling with the response of the cells to the inhibitors. Additional aliquots of cells from patient samples that respond in vitro will then be used in the NOD/SCID model of human leukemia to see if the inhibitors will also function in vivo. Cells which become resistant to FLT3 inhibitors in vitro or in vivo will be studied to determine the mechanisms that result in resistance. We hope that this work will help lead to clinical trials of these or similar compounds as novel therapeutics against leukemia.

描述（由申请人提供）：我们的长期目标是增加 治愈率并降低患者的化疗相关毒性 白血病。我们特别对患有白血病的患者感兴趣 由于突变或配体而激活的 FLT3 受体 共同表达。 20-40% 的 AML 患者存在 FLT3 突变 受体的预后特别差，治愈率只有 10-20% 儿童和成人人群的范围。这与治愈率形成鲜明对比 没有突变 FLT3 的 AML 患者为 40-50%。这使得发展 如果我们要实现对这些患者的新策略，就势在必行 他们的成果得到改善。 FLT3 受体最常见的突变形式包括小突变 (18-112 bp) 内部串联重复 (LTD)，每个重复都是唯一的 患者，但都映射到近膜区域，并且点突变影响 激酶结构域中的天冬氨酸 835。这两种突变都是组成型的 激活 FLT3 受体的酪氨酸激酶结构域，这是 信号传递和转换。通过从a中筛选>10,000个小分子 在基于细胞的测定中，我们已经确定了酪氨酸激酶抑制剂库 几种能够通过 IC50 完全抑制 FLT3 信号传导的化合物 在个位数 nM 范围内。 我们建议研究FLT3组成型激活的机制 并研究 FLT3 抑制剂如何干扰这些机制。的回应 使用 FLT3 抑制剂治疗的原代白血病细胞和细胞系将 研究了与联合使用时可能协同杀死细胞 将探索化疗。将在细胞中研究信号转导 系，并以更有限的方式在原代细胞中建立 信号传导变化与细胞响应的相关性 抑制剂。来自患者样本的额外等分细胞在 然后将体外用于人类白血病的 NOD/SCID 模型，看看是否 抑制剂也将在体内发挥作用。对 FLT3 产生抗性的细胞 将研究体外或体内抑制剂以确定其机制 从而产生阻力。我们希望这项工作将有助于临床试验 这些或类似的化合物作为抗白血病的新疗法。