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: 7373681
• 负责人: DONALD SMALL
• 金额: $ 29.36万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373681
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Adult; Affect; Alleles; Animal Model; Aspartic Acid; Behavior; Blood Cells; Cells; Childhood; Chromosomal translocation; Clinical; Clinical Trials; Cytogenetics; Data; Development; Diagnosis; Engineering; Enrollment; FLT3 gene; FLT3 inhibition; FLT3 inhibitor; Gene Mutation; Genes; Genetic; Goals; Hematopoietic; Homologous Gene; Human; Infection; Insertional Mutagenesis; Knock-in Mouse; Lead; Modeling; Molecular; Mus; Mutagenesis; Mutate; Mutation; Numbers; Oncogenes; Outcome; Patients; Pharmaceutical Preparations; Phenotype; Phosphotransferases; Point Mutation; Population; Proto-Oncogenes; Range; Rate; Receptor Protein-Tyrosine Kinases; Relapse; Reporting; Risk; Role; Sampling; Signal Transduction; Somatic Mutation; Staging; Stem cells; Structure-Activity Relationship; Testing; Time; Toxic effect; Toxicity due to chemotherapy; Transgenic Organisms; Transplantation; Tyrosine; Tyrosine Kinase Inhibitor; Up-Regulation; base; chemotherapy; improved; insertion/deletion mutation; leukemia; leukemogenesis; mutant; outcome forecast; pre-clinical; prognostic; promoter; response; retroviral-mediated; small molecule; stem; transcription factor

DESCRIPTION (provided by applicant): Our long-term goals are to increase the cure rate and decrease chemotherapy-related toxicity for patients with leukemia. FLT3 is a receptor tyrosine kinase that is one of the most frequently mutated genes in acute myeloid leukemia and is also less frequently mutated in ALL. The mutations result in constitutive activation of the kinase activity of FLT3 that contributes to transformation of normal hematopoietic cells. The group of patients with mutations has particularly poor outcomes with cure rates in the 10-20% range in pediatric and adult populations. While there are several gene alterations (mostly translocations involving transcription factors) known to occur together with FLT3 mutations, most FLT3 mutations occur in patients with normal karyotypes. It is likely that there are other second "hits" in these patients cooperating with FLT3 but the genes are likely affected by point mutations or small deletions or insertions that are not recognized by cytogenetics. One way to discover some of these genes is to determine the spectrum of genes that can cooperate with FLT3/ITD mutations in leukemogenesis. We will follow a strategy of retroviral insertion mutagenesis (RIM) in mice that we have engineered to express a FLT3/ITD mutation. We will also engineer a mouse that expresses a FLT3 kinase domain mutation and take a parallel approach to see if the phenotype of leukemia that results and spectrum of genes that cooperate are overlapping but different from the FLT3/ITD results as the behavior of AML patients with KD mutations is different from those with ITD mutations. We will then screen samples from patients with FLT3 mutant leukemias with normal cytogenetics for the presence of mutations or upregulation of these genes. We will also assess the response of the leukemias that develop in both types of mutant FLT3 mice to FLT3 tyrosine kinase inhibitors (TKI). Finally, we will determine the spectrum of activity of available FLT3 TKI against the many different types of KD mutations that have been reported in patients. Lay description: FLT3 is the most frequently mutated gene in acute myeloid leukemia and patients with this mutation have little chance for cure. We are studying how these mutations combine with alterations in other genes to cause normal blood cells to become leukemic. This will enable us to better attack these leukemias at the molecular level to improve the chance of cure and decrease the toxicities of chemotherapy.

描述（由申请人提供）：我们的长期目标是提高白血病患者的治愈率，降低化疗相关的毒性。FLT3是一种受体酪氨酸激酶，是急性髓性白血病中最常见的突变基因之一，在ALL中也不太常见。突变导致FLT3激酶活性的组成性激活，有助于正常造血细胞的转化。突变患者的预后特别差，儿科和成人的治愈率在10-20%之间。虽然已知有几种基因改变（主要是涉及转录因子的易位）与FLT3突变一起发生，但大多数FLT3突变发生在核型正常的患者中。在这些与FLT3配合的患者中，很可能存在其他的二次“命中”，但这些基因可能受到细胞遗传学无法识别的点突变或小缺失或插入的影响。发现其中一些基因的一种方法是确定在白血病发生中可以与FLT3/ITD突变合作的基因谱。我们将遵循逆转录病毒插入突变（RIM）的策略，我们已经设计表达FLT3/ITD突变的小鼠。我们还将设计一只表达FLT3激酶结构域突变的小鼠，并采用平行方法来观察白血病的表型和合作基因谱是否重叠，但与FLT3/ITD结果不同，因为患有KD突变的AML患者的行为不同于患有ITD突变的AML患者。然后，我们将从细胞遗传学正常的FLT3突变白血病患者中筛选这些基因是否存在突变或上调的样本。我们还将评估两种突变型FLT3小鼠对FLT3酪氨酸激酶抑制剂（TKI）的白血病反应。最后，我们将确定可用的FLT3 TKI对已报道的患者中许多不同类型的KD突变的活性谱。描述：FLT3是急性髓性白血病中最常见的突变基因，这种突变的患者几乎没有治愈的机会。我们正在研究这些突变是如何与其他基因的改变结合起来导致正常血细胞变成白血病的。这将使我们能够在分子水平上更好地攻击这些白血病，从而提高治愈的机会，减少化疗的毒性。