Targeting FLT3 as a Novel Specific Therapy for Leukemia

以 FLT3 为靶点作为白血病的新型特异性疗法

• 批准号: 6932110
• 负责人: MARK J LEVIS
• 金额: $ 13.85万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6932110
• 关键词: acute lymphocytic leukemia; acute myelogenous leukemia; antineoplastics; biological signal transduction; cell cycle; cell line; cell surface receptors; clinical research; clinical trials; cytotoxicity; drug screening /evaluation; gene expression; human subject; human therapy evaluation; kinase inhibitor; leukemia; neoplasm /cancer pharmacology; phosphorylation; protein tyrosine kinase; protooncogene

DESCRIPTION (provided by applicant): Leukemia remains a deadly disease in both adults and children. The majority of patients still die, and new treatments are urgently needed. There is now substantial data indicating that the receptor tyrosine kinase FLT3 plays a role in a significant fraction of leukemias. FLT3, which is expressed in most cases of acute myeloid and acute lymphocytic leukemia (AML and ALL), is constitutively activated by internal tandem duplication (ITD) mutations of the juxtamembrane region, by point mutations in the kinase domain, and by co-expression of FLT3 ligand (FL). 30% or more of AML cases harbor an activating mutation of FLT3, and this subset of patients has been shown to have a worse prognosis. Preliminary data presented here provides evidence that a FLT3 tyrosine kinase inhibitor is specifically cytotoxic to AML cells harboring FLT3 activating mutations. This proposal's scientific objective is the development of a FLT3 tyrosine kinase inhibitor for use in the treatment of leukemia. The immediate goal is to characterize the responses of different types of leukemias to the inhibitors in order to predict which patients may benefit from this therapy. The specific aims will be to test human leukemia cell lines and primary leukemic blasts for cytotoxic response to FLT3 inhibitors, with and without chemotherapy, and to correlate this cytotoxic response with changes in downstream signaling proteins and gene expression. Similar correlative studies will be performed on samples from patients receiving the inhibitor as part of a clinical trial. A FLT3 inhibitor has tremendous potential as an alternative or adjunct to conventional therapy for acute leukemias. This proposal has two goals. The first is to address the urgent need for new leukemia therapies. The second is to allow the principal investigator, Dr. Mark Levis, to develop into a laboratory-based researcher whose focus is to translate basic science research into clinical applications. With the guidance of a mentor who has expertise in the pathogenesis of leukemia, along with a structured educational program and a supportive academic environment, the principal investigator will use the support provided by this award to complete the transition to independent clinician scientist.

描述（由申请人提供）： 白血病仍然是成人和儿童的致命疾病。 大多数患者仍然死亡，迫切需要新的治疗方法。 现在有大量的数据表明受体酪氨酸激酶FLT3在很大一部分白血病中起作用。 在大多数急性髓细胞和急性淋巴细胞白血病（AML和ALL）病例中表达的FLT3通过质膜区域的内部串联重复（ITD）突变、激酶结构域的点突变和FLT3配体（FL）的共表达而组成性激活。 30%或更多的AML病例携带FLT3的激活突变，并且这部分患者的预后较差。 本文提供的初步数据证明，FLT3酪氨酸激酶抑制剂对携带FLT3激活突变的AML细胞具有特异性细胞毒性。 该提案的科学目标是开发用于治疗白血病的FLT3酪氨酸激酶抑制剂。 目前的目标是描述不同类型白血病对抑制剂的反应，以预测哪些患者可能从这种治疗中受益。 具体目标是测试人白血病细胞系和原代白血病母细胞对FLT3抑制剂的细胞毒性反应，有和没有化疗，并将这种细胞毒性反应与下游信号蛋白和基因表达的变化相关联。 作为临床试验的一部分，将对接受抑制剂的患者的样本进行类似的相关研究。 FLT3抑制剂作为急性白血病常规治疗的替代或辅助治疗具有巨大的潜力。 这项建议有两个目标。 首先是解决对新的白血病疗法的迫切需求。 二是让首席研究员Mark Levis博士发展成为一名以实验室为基础的研究人员，其重点是将基础科学研究转化为临床应用。 在具有白血病发病机制专业知识的导师的指导下，沿着结构化的教育计划和支持性的学术环境，主要研究者将利用该奖项提供的支持完成向独立临床科学家的过渡。