TYROSINE KINASE ONCOGENES IN ACUTE MYELOID LEUKEMIAS

急性髓系白血病中的酪氨酸激酶癌基因

• 批准号: 7394768
• 负责人: JAMES DOUGLAS GRIFFIN
• 金额: $ 30.23万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7394768
• 关键词: AML1-ETO fusion protein; Acute; Acute Myelocytic Leukemia; Affinity; Cells; Chronic; Clinical; Clinical Trials; Combined Modality Therapy; Dasatinib; Evaluation; FLT3 gene; FLT3 inhibition; FLT3 inhibitor; Generations; Goals; Grant; In Vitro; JAK2 gene; Leukemic Cell; Marrow; Mediating; Modeling; Mutate; Mutation; Myeloid Leukemia; Myeloproliferative disease; Neoadjuvant Therapy; Oncogene Proteins; Oncogenes; Outcome; PKC412; Pathogenesis; Pathway interactions; Patients; Pharmacotherapy; Phase; Phosphotransferases; Play; Polycythemia Vera; Pre-Clinical Model; Preclinical Testing; Principal Investigator; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Resistance; Role; Signal Pathway; Site; Standards of Weights and Measures; Stem cells; Stromal Cells; Testing; Therapeutic; Therapeutic Intervention; Tyrosine Kinase Inhibitor; Tyrosine-Kinase Oncogenes; chemotherapy; concept; cytotoxic; design; in vivo; in vivo Model; inhibitor/antagonist; kinase inhibitor; mutant; next generation; novel; programs; resistance mechanism; small molecule; therapeutic target

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.

这个PPG的长期目标是了解髓系白血病的发病机制和 骨髓增殖性疾病(MPD)，并利用这些信息开发新的有效治疗方法。它是 提出理想的治疗靶点是致癌基因的蛋白质产物，这些致癌基因可引起急性或 慢性髓系疾病，这项提案将继续侧重于酪氨酸激酶。在这个的最后一个周期里 Grant，这个项目的重点是了解Flt3突变在导致AML和其他疾病中所起的作用 验证突变的Flt3是药物治疗的有效靶点的概念。假设是抑制 对AML细胞有细胞毒作用，因此可能是 显著的治疗效益。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，至少有一种药物将进入第三阶段。 在合作小组环境中对AML和突变的Flt3患者进行诱导治疗的测试(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，以及 此外，建议启动针对髓样细胞中突变的另外两种酪氨酸激酶的具体的、重点的项目 白血病、KIT和JAK2。 该提案的主要重点仍然是FLT3，拟议的研究旨在测试 “联合靶向治疗”治疗急性髓细胞白血病的假说比使用一种激酶更有治疗价值 单独使用抑制剂。例如，我们预测，针对突变的癌基因，如flt3-itd，和 介导白血病细胞活性增强的关键下游通路，如PI3K，极有可能 要有协同性。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 成功后，我们希望对如何设计下一代Flt3有更好的理解 急性髓系白血病中的激酶抑制剂试验。 在另外两个更小、更具体的目标中，我们建议对另外两个酪氨酸激酶进行一些有针对性的研究 在急性髓系白血病(KIT)或真性红细胞增多症(JAK2)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，目标是开发临床试验，以后可以 在项目5中进行。