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: 6899859
• 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/6899859
• 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 治愈率和减少化疗相关毒性的患者 白血病特别是，我们感兴趣的患者的白血病表达 激活的FLT 3受体，无论是由于突变或配体 共表达20- 40%的AML患者携带FLT 3突变， 受体的治愈率特别低， 适用于儿童和成人人群。这与治愈率相比， 对于没有突变FLT 3的AML患者，为40- 50%。这使得发展 如果我们要有效地治疗这些病人， 改善他们的成果。 FLT 3受体中最常见的突变形式包括小的 （18-112 bp）内部串联重复（ITDs），其对于每一个都是独特的， 患者，但所有映射到质膜区域，和点突变影响 激酶结构域中的天冬氨酸835。这两种突变组成型 激活FLT 3受体的酪氨酸激酶结构域， 信号和转换。通过从一个小分子中筛选> 10，000个小分子 在基于细胞的测定中的酪氨酸激酶抑制剂库中，我们已经鉴定出 几种能够完全抑制FLT 3信号传导的化合物，IC 50 在单位数nM范围内。 我们建议研究FLT 3组成性激活的机制， 并研究FLT 3抑制剂如何干扰这些机制。响应 原代白血病细胞和细胞系用FLT 3抑制剂治疗， 研究和可能的协同杀死细胞时，结合 将探索化学疗法。信号转导将在细胞内进行研究 系，并且以更有限的方式，在原代细胞中，以建立 信号传导的变化与细胞对信号传导的响应的相关性。 抑制剂的来自患者样品的细胞的另外的等分试样，其响应于 然后将体外用于人白血病的NOD/SCID模型，以观察 抑制剂也将在体内起作用。对FLT 3产生耐药性的细胞 将研究体外或体内的抑制剂以确定 导致阻力。我们希望这项工作将有助于导致临床试验 这些或类似的化合物作为新的治疗白血病。