TYROSINE KINASE ONCOGENES IN ACUTE MYELOID LEUKEMIAS

该 PPG 的长期目标是了解髓性白血病和骨髓增殖性疾病 (MPD) 的发病机制，并利用这些信息开发新颖有效的疗法。有人提出，理想的治疗靶点是引起急性或慢性骨髓疾病的癌基因的蛋白质产物，该提案将继续关注酪氨酸激酶。在本次资助的最后一个周期中，该项目的重点是了解 FLT3 突变在引起 AML 中所起的作用，并测试突变型 FLT3 是药物治疗的有效靶点的概念。该假设是，抑制 FLT3 酪氨酸激酶活性对 AML 细胞具有细胞毒性，因此可能具有显着的治疗益处。我们在将两种 FLT3 抑制剂引入临床试验方面发挥了重要作用，早期阶段研究足以令人鼓舞，至少其中一种药物将在合作小组环境中对 AML 和突变 FLT3 患者进行诱导治疗中进行 III 期测试（参见项目 5）。在此，我们建议继续努力了解如何最佳地靶向突变型 FLT3，此外，建议启动针对髓系白血病中另外两种突变酪氨酸激酶（KIT 和 JAK2）的具体、重点项目。 该提案的主要焦点仍然是 FLT3，拟议的研究旨在检验以下假设：针对 AML 的“联合靶向治疗”比单独使用激酶抑制剂具有更高的治疗价值。例如，我们预测，针对突变癌基因（如 FLT3-ITD）和介导增强白血病细胞活力的关键下游途径（如 PI3K）很可能具有协同作用。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，我们希望能够更好地了解如何设计下一代 AML 中的 FLT3 激酶抑制剂试验。 在另外两个较小的具体目标中，我们建议对另外两种在 AML (KIT) 或真性红细胞增多症 (JAK2) 中发生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向，目标是开发随后在项目 5 中进行的临床试验。

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.