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: 7053083
• 负责人: DONALD SMALL
• 金额: $ 16.26万
• 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/7053083
• 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.

简介(由申请人提供)：我们的长期目标是增加 提高化疗治愈率降低化疗毒副反应 白血病。特别是，我们对白血病患者表现出的 由于突变或配体而激活的Flt3受体 共同表达。20%-40%的急性髓系白血病患者存在Flt3突变 受体的预后特别差，治愈率在10%-20%之间 适用于儿童和成人人群。与此形成鲜明对比的是 对于没有突变的Flt3的AML患者，40-50%。这使得发展 这些患者的新策略势在必行，如果我们要 他们的结果有所改善。 Flt3受体最常见的突变形式包括小分子 (18-112个碱基)内部串联复制(LTD)，每个LTD都是唯一的 患者，但全部映射到膜旁区域，并且点突变影响 天冬氨酸835在激活区。这两种突变都是结构性的 激活Flt3受体的酪氨酸激酶结构域，这是 信号和转换。通过从10,000个小分子中筛选 在基于细胞的分析中，我们已经确定了酪氨酸激酶抑制剂的文库 几种能够与IC50完全抑制Flt3信号转导的化合物 在个位数NM范围内。 我们建议研究Flt3被结构性激活的机制。 并研究Flt3抑制剂如何干扰这些机制。的回应 用Flt3抑制剂治疗的原代白血病细胞和细胞系 研究了联合使用时对细胞的可能协同杀伤作用 将探索化疗方法。信号转导将在细胞中进行研究 以更有限的方式，在原代细胞中，以建立 信号的变化与细胞对 抑制剂。从患者样本中提取的额外等量细胞 然后，体外将用于人类白血病的NOD/SCID模型，以了解 抑制剂也将在体内发挥作用。对Flt3产生抵抗力的细胞 体外或体内的抑制剂将被研究以确定其机制 会导致抵抗力。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治疗白血病的新疗法。