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: 9390456
• 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 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9390456
• 关键词: Acute Myelocytic Leukemia; Alleles; Animal Model; B-Cell Development; B-Lymphocytes; Biology; Blood; 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; Loss of Heterozygosity; Malignant Neoplasms; 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; Spleen; T-Lymphocyte; Time; Tumor Suppressor Proteins; Tyrosine Kinase Inhibitor; Work; adult leukemia; cancer type; chemotherapy; fetal liver kinase-2; improved; leukemia; leukemogenesis; mutant; outcome forecast; prognostic significance; public health relevance; response; targeted treatment

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。有些患者有很好的治愈机会，因为历史上我们知道，如果他们有某些染色体被改变，这些患者对化疗的反应很好。相反的情况也是如此。最近，我们已经能够发现某些基因的突变，这些突变给AML患者带来了相同的好或坏的治愈机会。人类的FLT 3基因是我的实验室在20年前克隆出来的。它是AML中最常见的突变基因。它不仅如此频繁地发生突变，而且最常见的FLT 3突变类型（称为ITD）也会给患有突变的AML患者带来非常严重的白血病治愈机会。例如，在儿童AML中，没有突变的患者有50-60%的治愈机会，但具有FLT 3/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逆转通过细胞中的FLT 3信号传递给白血病的非常致命的攻击性。我们解决这个问题的方法之一是找到第一种药物， 能够阻止C信号的产生。这被称为“酪氨酸激酶抑制剂”或TKI。我们发现，这将优先杀死具有FLT 3/ITD突变的白血病细胞，而不影响正常细胞。这些FLT 3 TKI的后代正在进行高级临床试验，试图提高FLT 3/ITD AML患者的治愈率。另一种类型的FLT 3突变，称为“激酶结构域”或KD突变，不会给AML患者带来更差的治愈机会。这让我们有机会尝试了解同一基因中的两种不同类型的突变如何导致如此不同的结果。如果我们能够理解FLT 3的ITD与KD突变如何不同地发出信号，它应该指出导致非常糟糕，难以治愈的白血病的途径。这些相同的途径很可能被其他白血病和其他类型的癌症所使用，因此识别它们将是第一步，然后针对它们来提高这些疾病的治愈率。由于白血病患者有如此多不同类型的突变组合，因此不可能区分出白血病患者之间的信号差异。 FLT 3/ITD vs. FLT 3/KD突变。为了克服这个问题，我们培育了小鼠，我们对它们进行了基因改造，使它们生来就具有两种类型突变中的任何一种。这些小鼠除了我们设计的FLT 3突变类型外，在遗传上是相同的，因此当我们将它们与产生白血病所需的相同“第二次打击”相结合时，白血病之间的任何差异都是FLT 3突变如何发挥作用的差异的结果。这将使我们能够确定是什么赋予ITD突变其“坏”特征。我们可以为这种“坏”途径开发靶向疗法，这种疗法可能被其他难以治愈的白血病和其他癌症所使用。

项目成果

Integration of Hedgehog and mutant FLT3 signaling in myeloid leukemia.

• DOI: 10.1126/scitranslmed.aaa5731
• 发表时间: 2015-06-10
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Lim Y;Gondek L;Li L;Wang Q;Ma H;Chang E;Huso DL;Foerster S;Marchionni L;McGovern K;Watkins DN;Peacock CD;Levis M;Smith BD;Merchant AA;Small D;Matsui W
• 通讯作者: Matsui W

Fluvastatin inhibits FLT3 glycosylation in human and murine cells and prolongs survival of mice with FLT3/ITD leukemia.

Fluvastatin 抑制人类和小鼠细胞中的 FLT3 糖基化，并延长 FLT3/ITD 白血病小鼠的生存期。

• DOI: 10.1182/blood-2012-01-403493
• 发表时间: 2012
• 期刊: Blood
• 影响因子: 20.3
• 作者: Williams,AllenB;Li,Li;Nguyen,Bao;Brown,Patrick;Levis,Mark;Small,Donald
• 通讯作者: Small,Donald

Effect of FLT3 ligand on survival and disease phenotype in murine models harboring a FLT3 internal tandem duplication mutation.

FLT3配体对携带FLT3内部串联重复突变的小鼠模型的生存和疾病表型的影响。

• 发表时间: 2013
• 期刊: Comparative medicine
• 影响因子: 0.8
• 作者: Bailey,EmilyJ;Duffield,AmyS;Greenblatt,SarahM;Aplan,PeterD;Small,Donald
• 通讯作者: Small,Donald

Dnmt3a deletion cooperates with the Flt3/ITD mutation to drive leukemogenesis in a murine model.

• DOI: 10.18632/oncotarget.11986
• 发表时间: 2016-10-25
• 期刊: Oncotarget
• 作者: Poitras JL;Heiser D;Li L;Nguyen B;Nagai K;Duffield AS;Gamper C;Small D
• 通讯作者: Small D

Combination of ATO with FLT3 TKIs eliminates FLT3/ITD+ leukemia cells through reduced expression of FLT3.

• DOI: 10.18632/oncotarget.25972
• 发表时间: 2018-08-31
• 期刊: Oncotarget
• 作者: Nagai K;Hou L;Li L;Nguyen B;Seale T;Shirley C;Ma H;Levis M;Ghiaur G;Duffield A;Small D
• 通讯作者: Small D