RNA Polymerase II as a Therapeutic Target in Acute Myeloid Leukemia (AML) with RAS Signaling Activation

RNA 聚合酶 II 作为急性髓系白血病 (AML) 的治疗靶点并激活 RAS 信号转导

• 批准号: 10657800
• 负责人: Catherine Choy Smith
• 金额: $ 53.49万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657800
• 关键词: Acute Myelocytic Leukemia; Address; Affect; American; BCL2 gene; Clinical; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Combined Modality Therapy; DNA Polymerase II; Dependence; Disease; FLT3 gene; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic Transcription; Goals; In Vitro; Induction of Apoptosis; Isocitrate Dehydrogenase; Leukemic Cell; Link; Malignant Neoplasms; Mediating; Mediator; Methods; Mitogen-Activated Protein Kinases; Mutate; Mutation; Newly Diagnosed; Oncogenic; Pathway interactions; Patients; Pattern; Phosphorylation; Phosphotransferases; Pre-Clinical Model; RNA; RNA Polymerase II; Recurrence; Refractory; Regulatory Element; Relapse; Research; Resistance; Resistance development; Role; Sampling; Signal Transduction; Therapeutic; Time; Transcription Coactivator; Transcription Factor AP-1; Translating; Tyrosine Kinase Inhibitor; Up-Regulation; Work; acute myeloid leukemia cell; combinatorial; efficacy evaluation; genome-wide; improved; in vivo; inhibitor; inhibitor therapy; mutant; new therapeutic target; non-genetic; novel; novel strategies; novel therapeutics; programs; relapse patients; resistance mechanism; response; small molecule inhibitor; targeted treatment; therapeutic target; therapeutically effective; therapy resistant; treatment strategy

PROJECT SUMMARY/ABSTRACT Background: Fms-Like Tyrosine Kinase 3 (FLT3) is the most commonly mutated gene in acute myeloid leukemia (AML) and mutations in FLT3 are associated with high relapse rates. FLT3 tyrosine kinase inhibitors (TKIs) are clinically active in FLT3-mutant AML but duration of response is limited by the development of resistance. Mutations in NRAS and other activation of the RAS pathway are major mechanisms of resistance to FLT3 inhibitors and other AML targeted therapies. Rationale: We have identified suppression of the Mediator/RNA Pol II pathway augments FLT3 TKI-induced apoptosis in the setting of RAS activation. The overall goals of this project are: (1) to prioritize therapeutic targets in the Mediator/RNA Pol II pathway; and (2) to determine the essential Mediator/RNA Pol II-dependent transcriptional targets relevant to FLT3 TKI resistance. Methods: We will identify essential components of the RNA Pol II pathway needed for TKI resistance in AML and evaluate the efficacy of existing RNA Pol II pathway inhibitors in MAPK-activated AML cells. We will determine RNA Pol II-dependent transcriptional changes induced by MAPK activation and FLT3 inhibition in pre-clinical models and patient samples. We will functionally validate the essential downstream transcriptional targets critical to RAS-mediated FLT3 TKI resistance in AML. Expected Results: These studies will rigorously evaluate RNA Pol II as a novel treatment strategy in AML with aberrant RAS/MAPK signaling. If successful, this strategy can be quickly translated to clinical trials in AML and this general approach may also prove efficacious in other RAS-mutant cancers.

项目摘要/摘要 背景：FMS样酪氨酸激酶3(Flt3)是急性髓系白血病中最常见的突变基因。 髓系白血病(AML)和Flt3基因突变与高复发率相关。Flt3 酪氨酸激酶抑制剂(TKIs)在Flt3突变的AML中临床上是有效的，但持续时间 反应受到抗性发展的限制。NRAS的突变和其他激活 RAS途径的改变是Flt3抑制剂和其他AML耐药的主要机制 有针对性的治疗。理论基础：我们已经确定了对Mediator/RNA Pol II的抑制 在RAS激活的背景下，通路增强了Flt3 TKI诱导的细胞凋亡。整体而言 该项目的目标是：(1)优先考虑Mediator/RNA Pol II途径中的治疗靶点； 和(2)确定依赖于基本介体/RNA POL II的转录靶标 与Flt3 TKI耐药相关。方法：我们将鉴定RNA Pol的基本成分 急性髓系白血病TKI耐药所需的II通路及现有RNA Pol II的疗效评价 MAPK激活的急性髓系白血病细胞中的通路抑制剂。我们将确定RNA POL II依赖于 MAPK激活和Flt3抑制在临床前模型中诱导的转录变化 和病人样本。我们将从功能上验证必要的下游转录 AML中RAS介导的Flt3 TKI耐药的关键靶点。预期结果：这些研究 将严格评估RNA Pol II作为一种治疗AML异常的新策略 RAS/MAPK信令。如果成功，这一策略可以迅速转化为临床试验 AML和这种一般方法在其他RAS突变癌症中也可能被证明是有效的。