FLT3 Tyrosine Kinase Inhibitors as Therapy for Leukemia

描述(申请人提供)：急性髓系白血病(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，因为从历史上看，我们知道，如果他们的某些染色体发生了变化，这些患者对化疗的反应很好。相反的情况也是如此。最近，我们已经能够在某些基因上发现突变，这些突变给AML患者带来了同样好的或坏的治愈机会。我的实验室在大约20年前克隆了名为flt3的人类基因。事实证明，它是急性髓细胞白血病中最常见的突变基因。不仅它经常发生突变，而且最常见的一种Flt3突变(称为ITD)也会导致一种非常侵袭性的白血病，对于具有这种突变的AML患者来说，治愈的机会非常小。例如，在儿科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，通过Flt3在细胞中发出信号来逆转赋予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是找到第一批 能够阻止c信号。这被称为“酪氨酸酶抑制剂”或TKI。我们证明，这将优先杀死带有Flt3/ITD突变的白血病细胞，而不会影响正常细胞。这些新一代的Flt3 TKI正在进行高级临床试验，试图提高Flt3/ITD AML患者的治愈率。另一种类型的Flt3突变，称为“激酶域”或KD突变，并不会给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Flt3的ITD和KD突变是如何不同地传递信号的，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。因为患者白血病有如此多不同类型突变的组合，所以不可能区分不同类型之间的信号差异。 这些突变是由于Flt3/ITD与Flt3/KD突变所致。为了解决这个问题，我们培育了小鼠，我们通过基因工程使它们出生时带有两种类型的突变中的任何一种。除了我们设计的Flt3突变类型外，这些小鼠在基因上是相同的，所以当我们将它们与产生白血病所需的相同“二次命中”结合时，白血病之间的任何差异都是由于flt3突变如何发挥作用的不同造成的。这将使我们能够确定是什么赋予了ITD突变“坏”的特征。我们可以为这种“坏”途径开发有针对性的疗法，这种途径很可能被其他难以治愈的白血病甚至其他癌症所使用。

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.