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: 10302179
• 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/10302179
• 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/antagonist; 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 急性髓性白血病（AML）占儿童白血病病例的20%。与急性淋巴细胞性相比， 尽管急性淋巴细胞白血病（ALL）的治愈率仍然很低，大多数患者死于难治性白血病或 治疗相关毒性。与老年人AML相反，儿童AML的全基因组研究， 青少年和年轻人（AYA）显示较低的突变负担和高度流行的转录 因子融合和RAS途径突变。此外，虽然转录因子融合被假设为 促进允许AML发展的转录签名，实验数据表明， 信号传导突变在体内驱动白血病生长中起中心作用。因此，同时针对 在AML中异常的转录程序和异常的信号通路是合理的治疗方法 这在儿童和AYA患者中尤其重要。 该提案的总体目标是研究有希望的药物组合的功效， 同时靶向儿童AML关键通路并阐明药物潜在分子机制 （1）通过以下具体目标， 验证药物协同作用和对BET + MEK抑制的抗性的机制;以及（2）研究药物协同作用的机制。 在儿科AML的患者来源的异种移植物（PDX）模型中该组合的体内功效。