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Incorporating FLT3 inhibitors into AML treatment regimens

将 FLT3 抑制剂纳入 AML 治疗方案

基本信息

批准号：
8249113
负责人：
MARK J LEVIS
金额：
$ 33.01万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
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

项目摘要

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. 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.

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更差的临床结果相关。几种不同的小分子FLT3抑制剂，在AML患者中进行了研究，大多数研究表明，有限但一致的临床活性。我们以前的研究表明，FLT3抑制结合化疗导致对FLT3突变AML细胞的协同细胞毒性作用，并且FLT3 突变存在于白血病干细胞（LSC）中。正在进行的FLT3临床研究的初步结果复发性AML患者中的FLT3抑制剂表明，化疗后成功抑制FLT3，临床获益。然而，目前尚不清楚抑制剂对FLT3的选择性如何，何时以及如何选择在治疗过程中是否应该给予它们，以及它们是否对LSC有效。我们先前已经成功地在临床前模拟了掺入FLT3抑制剂的AML治疗方案，并且该提议旨在在几个不同的临床试验的背景下扩展该工作。的广泛目标该提案旨在更好地了解如何将FLT3抑制纳入AML治疗， FLT3突变AML的存活率或治愈率。具体的目标将是使用来自AML的原代白血病细胞患者，包括参加FLT3抑制剂试验的患者，以研究选择性和非选择性 FLT3抑制剂，单独使用和与不同化疗序列联合使用，对抗大量白血病细胞和白血病干细胞和祖细胞。入组患者的血浆 FLT3抑制剂试验将用于通过测量FLT3血浆浓度来研究FLT3抑制的疗效。抑制活性这些使用试验患者的原始胚细胞样本和血浆的研究结果将与临床结果相关。 Lay描述：一种被称为FLT3的基因在大约三分之一的急性髓细胞白血病细胞中发生突变。白血病（AML）病例，与缺乏这种治疗的患者相比，这种患者的预后非常差。突变正在开发被称为FLT3抑制剂的新药，以靶向这些FLT3突变。我们长期目标是学习如何将这些药物纳入目前的治疗方案，以改善 FLT3突变AML患者的治愈率和延长生存期。许多急性髓性白血病（AML）患者的FLT3基因发生突变，这使得患者的病情恶化。预后该提案旨在将FLT3靶向治疗纳入AML治疗，提高这些患者的生存率。