Incorporating FLT3 Inhibitors into AML Treatment Regimens

将 FLT3 抑制剂纳入 AML 治疗方案

• 批准号: 7468679
• 负责人: MARK J LEVIS
• 金额: $ 26.77万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7468679
• 关键词: Achievement; Acute Myelocytic Leukemia; Address; Animal Model; BAY 54-9085; Biological Models; Blast Cell; Cells; Chemicals; Class; Clinical; Clinical Research; Clinical Trials; Condition; Disease remission; Enrollment; FLT3 gene; FLT3 inhibition; FLT3 inhibitor; Genes; Goals; In Vitro; Learning; Maintenance Therapy; Malignant Neoplasms; Measurement; Modeling; Molecular Abnormality; Mutate; Mutation; Numbers; Outcome; Patients; Peripheral; Pharmaceutical Preparations; Plasma; Range; Rate; 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

Activating mutations in the FLT3 receptor tyrosine kinase are the most common molecular abnormality in AMI and are associated with significantly worse clinical outcomes. Several different small molecule FLT3 nhibitors, 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 nhibition 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 ncorporating 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.

FLT3受体酪氨酸激酶的激活突变是最常见的分子异常， 急性心肌梗死与临床结局显著恶化相关。几种不同的小分子FLT3 对FLT3的选择性差异很大的抑制剂已经在AML患者中进行了研究，大多数抑制剂 显示出有限但一致的临床活性。我们以前的研究表明，FLT3抑制 联合化疗导致对FLT3突变AML细胞的协同细胞毒性作用， FLT3突变存在于白血病干细胞（LSC）中。正在进行的临床研究的初步结果 FLT3抑制剂在复发性AML患者中的应用表明，化疗后成功的FLT3 nursing导致临床益处。然而，目前还不知道抑制剂对FLT3的选择性如何， 在治疗过程中，应在何时给予这些药物以及给予多长时间，以及这些药物是否有效 针对LSC。我们之前已经成功地在临床前建模AML治疗方案 结合FLT3抑制剂，这项建议的目的是在几个不同的背景下扩展这项工作， 临床试验该提案的广泛目标是更好地了解如何将FLT3抑制纳入 AML治疗，以提高FLT3突变AML的存活率或治愈率。具体目标是利用 AML患者的原代白血病细胞，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抑制剂单独和与不同序列的 在体外和动物实验中， 模型入组FLT3抑制剂试验的患者的血浆将用于研究FLT3的疗效 通过测量FLT3血浆抑制活性测定FLT3抑制。这些研究的结果使用主要 来自试验患者的原始细胞样品和血浆将与临床结果相关。 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，与那些缺乏AML的患者相比，这部分患者的预后非常差。 这个突变。正在开发被称为FLT3抑制剂的新药，以靶向这些FLT3突变。 我们的长期目标是学习如何将这些药物纳入当前的治疗方案， 提高FLT3突变AML患者的治愈率并延长生存期。