Incorporating FLT3 inhibitors into AML treatment regimens

将 FLT3 抑制剂纳入 AML 治疗方案

• 批准号: 7587474
• 负责人: MARK J LEVIS
• 金额: $ 34.03万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587474
• 关键词: Acute Myelocytic Leukemia; Address; Animal Model; Biological Models; Blast Cell; Cells; Chemicals; Clinical; Clinical Research; Clinical Trials; Disease; Enrollment; FLT3 gene; FLT3 inhibition; FLT3 inhibitor; Genes; Goals; In Vitro; Learning; Malignant Neoplasms; Measurement; Modeling; Molecular Abnormality; Mutate; Mutation; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Phosphotransferases; Plasma; Receptor Protein-Tyrosine Kinases; Relapse; Resistance; Sampling; Stem cells; Toxic effect; Treatment Protocols; Tyrosine Kinase Inhibitor; Work; chemotherapeutic agent; chemotherapy; clinical effect; cytotoxic; improved; in vitro Model; inhibitor/antagonist; killings; leukemia; leukemic stem cell; mutant; outcome forecast; response; small molecule; stem; success

DESCRIPTION (provided by applicant): Activating mutations in the FLT3 receptor tyrosine kinase are the most common molecular abnormality in AML and are associated with significantly worse clinical outcomes. Several different small molecule FLT3 inhibitors, which vary considerably in selectivity for FLT3, have been studied in AML patients, and most have shown limited but consistent clinical activity. Our previous studies have demonstrated that FLT3 inhibition combined with chemotherapy leads to synergistic cytotoxic effects against FLT3 mutant AML cells, and that FLT3 mutations are present in leukemia stem cells (LSCs). Preliminary results from ongoing clinical studies of FLT3 inhibitors in relapsed AML patients suggest that chemotherapy followed by successful FLT3 inhibition leads to clinical benefit. However, it is not known how selective for FLT3 the inhibitors should be, when and for how long in the course of therapy they should be given, and whether or not they are effective against LSCs. We have previously succeeded in pre-clinically modeling AML treatment regimens incorporating FLT3 inhibitors, and this proposal aims to extend this work in the context of several different clinical trials. The broad goal of this proposal is to better understand how to incorporate FLT3 inhibition into AML therapy so as to improve survival or cure rates for FLT3 mutant AML. The specific goals will be to use primary leukemia cells from AML patients, including those enrolled on FLT3 inhibitor trials, to study the efficacy of selective and non-selective FLT3 inhibitors, alone and in combination with different sequences of chemotherapy, against bulk leukemia cells and leukemia stem and progenitor cells using in vitro and animal models. Plasma from patients enrolled on FLT3 inhibitor trials will be used to study the efficacy of FLT3 inhibition via measurement of FLT3 plasma inhibitory activity. The results of these studies using primary blast samples and plasma from trial patients will be correlated with clinical outcomes. Lay description: A gene known as FLT3 is mutated in the leukemia cells of about one third of acute myeloid leukemia (AML) cases, and this subset of patients has a very poor prognosis compared to those who lack this mutation. New drugs, known as FLT3 inhibitors, are being developed to target these FLT3 mutations. Our long-term goal is to learn how to incorporate these drugs into current treatment regimens in order to improve the cure rate and prolong survival for AML patients with FLT3 mutations. PUBLIC HEALTH RELEVANCE: Many patients with acute myeloid leukemia (AML) have mutations in the FLT3 gene, which confer a worse prognosis. This proposal is aimed at incorporating a FLT3-targeted therapy into AML treatment so as to improve survival for these patients.

描述（由申请人提供）：FLT3受体酪氨酸激酶的激活突变是AML中最常见的分子异常，并且与显著较差的临床结果相关。几种不同的小分子FLT3抑制剂，对FLT3的选择性差异很大，已经在AML患者中进行了研究，大多数显示出有限但一致的临床活性。我们之前的研究表明，FLT3抑制联合化疗可对FLT3突变的AML细胞产生协同细胞毒作用，并且FLT3突变存在于白血病干细胞（LSCs）中。正在进行的FLT3抑制剂在复发性AML患者中的临床研究的初步结果表明，化疗后成功抑制FLT3可带来临床获益。然而，目前尚不清楚这些抑制剂对FLT3的选择性如何，在治疗过程中何时和持续多长时间，以及它们对LSCs是否有效。我们之前已经成功地对含有FLT3抑制剂的AML治疗方案进行了临床前建模，本提案旨在将这项工作扩展到几个不同的临床试验中。该提案的总体目标是更好地了解如何将FLT3抑制纳入AML治疗，从而提高FLT3突变型AML的生存率或治愈率。具体目标将是使用来自AML患者的原发性白血病细胞，包括那些参加FLT3抑制剂试验的患者，在体外和动物模型中研究选择性和非选择性FLT3抑制剂单独或与不同序列的化疗联合对大量白血病细胞和白血病干细胞和祖细胞的疗效。参加FLT3抑制剂试验的患者的血浆将通过测量FLT3血浆抑制活性来研究FLT3抑制的效果。这些研究使用来自试验患者的原始细胞样本和血浆的结果将与临床结果相关。描述：在大约三分之一的急性髓性白血病（AML）病例中，一种被称为FLT3的基因在白血病细胞中发生突变，与那些没有这种突变的患者相比，这部分患者的预后非常差。新的药物，被称为FLT3抑制剂，正在开发针对这些FLT3突变。我们的长期目标是学习如何将这些药物纳入当前的治疗方案，以提高FLT3突变AML患者的治愈率并延长生存期。公共卫生相关性：许多急性髓性白血病（AML）患者有FLT3基因突变，这导致预后较差。该建议旨在将flt3靶向治疗纳入AML治疗，以提高这些患者的生存率。