TYROSINE KINASE ONCOGENES IN ACUTE MYELOID LEUKEMIAS

该PPG的长期目标是了解髓系白血病的发病机制， 骨髓增生性疾病（MPD），并使用这些信息来开发新的和有效的治疗方法。是 提出治疗的理想靶点是引起急性或慢性炎症的癌基因的蛋白质产物， 慢性骨髓性疾病，该提案将继续关注酪氨酸激酶。在上一个周期中， 该项目的重点是了解FLT 3突变在导致AML中的作用， 测试突变FLT 3是药物治疗的有效靶点的概念。假设是抑制 的FLT 3酪氨酸激酶活性将对AML细胞具有细胞毒性，因此可能是 显著的治疗益处。我们在将两种FLT 3抑制剂引入临床试验方面发挥了重要作用， 早期阶段的研究足以令人鼓舞，至少有一种药物将进入III期 在协作组环境中对AML和突变的FLT 3患者进行诱导治疗的测试（参见 项目5）。在这里，我们建议继续努力了解如何最佳靶向突变FLT 3， 此外，还建议启动针对骨髓中另外两种突变酪氨酸激酶的具体、重点项目， 白血病、KIT和JAK 2。 该提案的主要重点仍然是FLT 3，拟议的研究旨在测试 AML“联合靶向治疗”比使用激酶更有治疗价值的假设 单独抑制剂。例如，我们预测，靶向突变癌基因，如FLT 3-ITD， 介导白血病细胞活力增强的关键下游途径，如PI 3 K，很可能 是协同的。我们还将开发更高亲和力的抑制剂，并仔细研究耐药机制。如果 成功，我们希望有一个更好的了解如何设计下一代的FLT 3 AML中的激酶抑制剂试验 在另外两个较小的具体目标中，我们提出了对另外两种酪氨酸激酶的一些重点研究， 在AML（KIT）或真性红细胞增多症（JAK 2）中发生突变。这些研究将探索治疗 在临床前模型中靶向这些激酶，目的是开发临床试验， 在项目5中进行。

The long-term goals of this PPG are to understand the pathogenesis of myeloid leukemias and myeloproliferative disorders (MPDs) and use this information to develop novel and effective therapies. It is proposed that the ideal targets for therapy are the protein products of the oncogenes that cause acute or chronic myeloid diseases, and this proposal will continue to focus on tyrosine kinases. In the last cycle of this grant, this project focused on understanding the role that mutations in FLT3 play in causing AML and on testing the concept that mutant FLT3 was a valid target for drug therapy. The hypothesis was that inhibition of FLT3 tyrosine kinase activity would be cytotoxic for AML cells and would therefore potentially be of significant therapeutic benefit. We were instrumental in bringing two FLT3 inhibitors to clinical trials, and early phase studies were sufficiently encouraging that at least one of these agents will undergo phase III testing in induction therapy of patients with AML and mutated FLT3 in a cooperative group setting (see project 5). Here, we propose to continue our efforts to understand how to optimally target mutant FLT3, and in addition, propose to initiate specific, focused projects on two other tyrosine kinases mutated in myeloid leukemias, KIT and JAK2. The major focus of the proposal remains on FLT3, The proposed studies are aimed at testing the hypothesis that "combination targeted therapy" for AML has more therapeutic value than use of a kinase inhibitor alone. For example, we predict that targeting both a mutant oncogene, such as FLT3-ITD, and a critical downstream pathway mediating enhanced viability of leukemic cells, such as PI3K, is highly likely to be synergistic. We will also develop higher affinity inhibitors and carefully study resistance mechanisms. If successful, we hope to have a much better understanding of how to design the next generation of FLT3 kinase inhibitor trials in AML. In two other, smaller, specific aims, we propose some focused studies on two other tyrosine kinases that are mutated in either AML (KIT) or Polycythemia Vera (JAK2). These studies will explore therapeutic targeting of these kinases in preclinical models, with the goal of developing clinical trials that can later be conducted in Project 5.