FLT3 Tyrosine Kinase Inhibitors as Therapy for Leukemia

FLT3 酪氨酸激酶抑制剂治疗白血病

• 批准号: 8627818
• 负责人: DONALD SMALL
• 金额: $ 29.16万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8627818
• 关键词: Acute Myelocytic Leukemia; Alleles; Animal Model; B-Cell Development; B-Lymphocytes; Biology; Blood; Breeding; Cells; Characteristics; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Chromosomes; Clinical; Clinical Trials; DNA Double Strand Break; Data; Development; Diagnosis; Disease; Double Strand Break Repair; Engineering; Generations; Genes; Genetic Engineering; Genetically Engineered Mouse; Grant; Hematopoietic; Human; Human Cloning; Investigation; Knock-in Mouse; Knowledge; Lead; Learning; Left; Loss of Heterozygosity; Malignant Neoplasms; Maps; Mediating; Mus; Mutant Strains Mice; Mutate; Mutation; Myelogenous; Nature; Normal Cell; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphotransferases; Point Mutation; Process; Relapse; Role; Signal Transduction; Sorting - Cell Movement; Spleen; Staging; T-Lymphocyte; Time; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Work; adult leukemia; cancer type; chemotherapy; fetal liver kinase-2; improved; killings; leukemia; leukemogenesis; mouse model; mutant; outcome forecast; prognostic; public health relevance; response

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is the most common type of adult leukemia and second most common form of childhood leukemia. Some patients have a good chance of cure because historically we know that if they have certain chromosomes that are altered, those patients have done well in response to chemotherapy. The opposite case is also true. More recently we have been able to find mutations in certain genes that give these same good or bad chances for cure to patients with AML. The human gene called FLT3 was cloned by my lab about 20 years ago. It turns out to be the most frequently mutated gene in AML. Not only is it so frequently mutated, but the most common type of FLT3 mutation (called ITD) also gives a very aggressive leukemia with a horrible chance of cure for the AML patients who have the mutation. For example, in pediatric AML, patients without the mutation have a 50-60% chance of cure but those with a FLT3/ITD mutation have only a 15-20% chance of cure. Thus, to improve the chance for curing these patients we need to find ways to reverse the very lethal aggressive nature imparted to the leukemia by way that FLT3 signals in the cell. One of the ways we have attacked this problem was to find the first drugs that were able to block how c signals. This is called a "tyrosine kinase inhibitor" or TKI. We showed that this would preferentially kill leukemia cells with the FLT3/ITD mutation while leaving normal cells alone. Later generations of these FLT3 TKI are in advanced clinical trials to try to improve the cure rate for FLT3/ITD AML patients. Another type of FLT3 mutation, called a "kinase domain" or KD mutation, does not give patients with AML a worse chance for cure. This gives us the opportunity to try to learn how the 2 different kinds of mutations in the same gene can lead to such different outcomes. If we can understand how the ITD vs. KD mutations of FLT3 signal differently, it should point out the pathway that results in really bad, difficult to cure leukemias. These same pathways are likely to be used by other leukemias and possibly other types of cancers and so identifying them will be the first step followed by targeting them to improve the cure rate for these diseases. Because patient leukemias have combinations of so many different types of mutations, it is not possible to sort out the signaling differences between them that are due to FLT3/ITD vs. FLT3/KD mutations. To overcome this problem we have generated mice in which we genetically engineered them to be born with either of the two types of mutations. These mice are genetically identical other than the type of FLT3 mutations we have engineered so when we combine them with the same "second hits" required to generate leukemia any differences between the leukemias are a result of differences in how the FLT3 mutations function. This will enable us to determine what gives the ITD mutations its "bad" characteristics. We can develop targeted therapies for this "bad" pathway that is likely used by other difficult to cure leukemias and perhaps other cancers.

描述（由申请人提供）：急性髓性白血病（AML）是成人白血病中最常见的类型，也是儿童白血病中第二常见的类型。有些病人有很好的治愈机会，因为历史上我们知道，如果他们的某些染色体发生了改变，这些病人对化疗的反应就很好。反之亦然。最近，我们已经能够在某些基因中发现突变，这些突变给AML患者带来了同样好的或坏的治愈机会。人类基因FLT3是我的实验室在大约20年前克隆出来的。它是AML中最常见的突变基因。它不仅经常发生突变，而且最常见的FLT3突变类型（称为ITD）也会给患有这种突变的AML患者带来非常严重的白血病，治愈的机会非常渺茫。例如，在儿童AML中，没有突变的患者有50-60%的治愈机会，但那些有FLT3/ITD突变的患者只有15-20%的治愈机会。因此，为了提高治愈这些患者的机会，我们需要找到方法来扭转通过细胞中FLT3信号传递给白血病的非常致命的侵袭性。我们解决这个问题的方法之一就是找到第一批药物