Co-targeting BET Bromodomain Proteins and Aberrant Signaling in AML.

共同靶向 BET 溴结构域蛋白和 AML 中的异常信号传导。

• 批准号: 10454383
• 负责人: Benjamin Huang
• 金额: $ 24.8万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454383
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Adolescent and Young Adult; Adult Acute Myeloblastic Leukemia; Alternative Therapies; Apoptosis; Automobile Driving; Biological Models; Bromodomain; CRISPR interference; Cell Line; Chemotherapy-Oncologic Procedure; Child; Childhood Acute Myeloid Leukemia; Childhood Leukemia; Clinical; Combined Modality Therapy; Data; Dependence; Development; Diagnosis; Drug Combinations; Drug Synergism; Drug resistance; Elderly; Epigenetic Process; Gene Expression Profile; Genes; Genetic; Genetic Heterogeneity; Genetic Transcription; Genomics; Goals; Growth; Human; Immunocompetent; Insertional Mutagenesis; KRAS2 gene; Knowledge; Laboratories; Leukemic Cell; MEK inhibition; MEKs; MLL gene; Malignant Neoplasms; Methodology; Modeling; Molecular; Mus; Mutation; NF1 mutation; Outcome; Pathway interactions; Patients; Play; Proliferating; Proteins; Ras Signaling Pathway; Refractory; Relapse; Resistance; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Somatic Mutation; System; TP53 gene; Testing; Therapeutic; Translating; Transplantation; Treatment-related toxicity; Work; acute myeloid leukemia cell; base; cohort; congenic; drug testing; experimental study; genome-wide analysis; hyperactive Ras; in vivo; inhibitor; knock-down; leukemia; leukemia relapse; leukemic transformation; mouse model; mutant; next generation; overexpression; patient derived xenograft model; pediatric patients; programs; resistance mechanism; response; synergism; transcription factor; transcriptome sequencing; tumor; validation studies

PROJECT SUMMARY Acute myeloid leukemia (AML) comprises 20% of childhood leukemia cases. In contrast to acute lymphoblastic leukemia (ALL), cure rates for AML remain poor with the majority of patients dying from refractory leukemia or treatment related toxicities. In contrast to AML in older adults, genome-wide studies of AML in children, adolescents, and young adults (AYA) revealed a lower mutational burden and highly prevalent transcription factor fusions and RAS pathway mutations. Additionally, while transcription factor fusions are hypothesized to promote a transcriptional signature that is permissive for AML development, experimental data suggest that signaling mutations play a central role in driving leukemic growth in vivo. Thus, simultaneously targeting the abnormal transcriptional program and aberrant signaling pathways in AML is a rational therapeutic approach that is particularly relevant in children and AYA patients. The overall goals of this proposal are to investigate the efficacy of promising drug combinations that simultaneously target key pathways in pediatric AML and to elucidate molecular mechanisms underlying drug synergy and resistance to these targeted approaches through the following specific aims: (1) to identify and validate mechanisms of drug synergy and resistance to BET + MEK inhibition; and, (2) to investigate the in vivo efficacy of this combination in patient derived xenograft (PDX) models of pediatric AML.

项目摘要 急性髓样白血病（AML）占儿童白血病病例的20％。与急性淋巴细胞相比 白血病（ALL），AML的治疗率仍然很差，大多数患者死于难治性白血病或 治疗相关的毒性。与老年人中的AML相反，儿童全基因组的AML研究 青少年和年轻人（AYA）显示出较低的突变负担和高度普遍的转录 因子融合和RAS途径突变。另外，虽然转录因子融合被假设为 促进允许AML开发的转录签名，实验数据表明 信号传导突变在驱动体内的白血病生长方面起着核心作用。因此，同时定位 AML中的异常转录程序和异常信号通路是一种合理的治疗方法 这在儿童和AYA患者中尤其重要。 该提案的总体目标是调查有希望的药物组合的功效 同时靶向小儿AML中的关键途径，并阐明药物的分子机制 通过以下特定目的进行协同和对这些目标方法的抵抗：（1）识别和 验证药物协同作用的机制和对BET + MEK抑制的抵抗力； （2）调查IN 该组合在儿科AML的患者衍生异种移植（PDX）模型中的体内功效。