FLT3 Tyrosine Kinase Inhibitors as Therapy for Leukemia

FLT3 酪氨酸激酶抑制剂治疗白血病

基本信息

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
项目类别：
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

项目摘要

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治疗率并降低对白血病患者的化学疗法毒性。 FLT3是一种受体酪氨酸激酶，它是急性髓样白血病中最常见的突变基因之一，并且在所有急性突变中也较少突变。该突变导致FLT3的激酶活性的组成型激活有助于正常造血细胞的转化。突变患者组的预后较差，在儿科和成人人群中的治愈率范围为10-20％。尽管已知与FLT3突变一起发生的几种基因改变（主要是涉及转录因子的易位），但大多数FLT3突变发生在正常核型患者中。这些患者与FLT3配合的患者中可能还有其他第二个“命中”，但这些基因可能受到点突变，小缺失或插入的影响，而这些基因未被细胞遗传学识别。发现其中一些基因的一种方法是确定可以在白血病中与FLT3/ITD突变合作的基因谱。我们将遵循我们已设计为表达FLT3/ITD突变的小鼠逆转录病毒插入诱变（RIM）的策略。我们还将设计一种表达FLT3激酶结构域突变的小鼠，并采用平行的方法，以查看白血病的表型是否会导致合作的基因和频谱重叠，但与FLT3/ITD的结果与FLT3/ITD的结果不同，因为AML具有KD突变患者的行为与ITD突变的AML患者的行为不同。然后，我们将筛选来自FLT3突变体白血病患者的样品，具有正常的细胞遗传学，以存在突变或上调这些基因。我们还将评估两种突变体FLT3小鼠在FLT3酪氨酸激酶抑制剂（TKI）中发展的白血病的反应。最后，我们将确定可用的FLT3 TKI活性范围对患者报告的许多不同类型的KD突变。外行描述：FLT3是急性髓样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如何与其他基因的改变相结合，导致正常血细胞成为白血病。这将使我们能够在分子水平上更好地攻击这些白血病，以提高治愈的机会并减少化学疗法的毒性。