TYROSINE KINASE ONCOGENES IN ACUTE MYELOID LEUKEMIAS

该PPG的长期目标是了解髓系白血病和骨髓增生性疾病(MPDS)的发病机制，并利用这些信息开发新的有效治疗方法。有人建议，理想的治疗靶点是导致急性或慢性髓系疾病的癌基因的蛋白产物，这一提议将继续侧重于酪氨酸激酶。在这笔赠款的最后一个周期，这个项目的重点是了解Flt3突变在导致AML中所起的作用，并测试突变的flt3是药物治疗的有效靶点这一概念。假说是，抑制Flt3酪氨酸激酶活性对AML细胞具有细胞毒性，因此可能具有显著的治疗益处。我们帮助将两种Flt3抑制剂带入临床试验，早期研究充分鼓舞人心，这些药物中至少有一种将在合作小组环境下对AML和突变的Flt3患者进行诱导治疗的III期测试(见项目5)。在这里，我们建议继续努力了解如何最佳地靶向突变的Flt3，此外，我们还建议启动针对髓系白血病中突变的另外两种酪氨酸激酶KIT和JAK2的特定的、集中的项目。 该提案的主要关注点仍然是Flt3，拟议的研究旨在验证这样一种假设，即AML的“联合靶向治疗”比单独使用激酶抑制剂具有更大的治疗价值。例如，我们预测，针对突变的癌基因，如Flt3-ITD，以及介导白血病细胞活性增强的关键下游途径，如PI3K，很可能是协同作用的。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，我们希望对如何在AML中设计下一代Flt3激酶抑制剂试验有更好的理解。 在另外两个较小的、特定的目标中，我们建议对另外两个在AML(KIT)或真性红细胞增多症(JAK2)中突变的酪氨酸激酶进行一些重点研究。这些研究将探索这些激酶在临床前模型中的治疗靶点，目标是开发临床试验，稍后可以在项目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.