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

基本信息

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
项目类别：
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

项目摘要

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）是急性最常见的突变基因 FLT3中的髓样白血病（AML）和突变与高复发率有关。 flt3 酪氨酸激酶抑制剂（TKI）在FLT3突变AML中具有临床活性，但持续时间为反应受到阻力发展的限制。 NRA和其他激活中的突变 RAS途径的主要机制是对FLT3抑制剂和其他AML的抗性靶向疗法。理由：我们已经确定了对介体/RNA Pol II的抑制在RAS激活的情况下，途径增加了FLT3 TKI诱导的凋亡。总体该项目的目标是：（1）优先考虑调解人/RNA POL II途径中的治疗靶标；（2）确定基本介体/RNA POL II依赖性转录靶标与FLT3 TKI抗性有关。方法：我们将确定RNA POL的基本组成部分 TKI在AML中所需的II途径并评估现有RNA POL II的功效 MAPK激活的AML细胞中的途径抑制剂。我们将确定RNA POL II依赖性在临床前模型中，MAPK激活和FLT3抑制引起的转录变化和患者样品。我们将在功能上验证必需的下游转录对于AML中RAS介导的FLT3 TKI抗性至关重要的目标。预期结果：这些研究将严格评估RNA POL II作为AML的新型治疗策略 RAS/MAPK信号。如果成功，则可以将此策略快速转化为临床试验 AML和这种通用方法也可能在其他RAS突变癌中有效。