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。

基本信息

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
项目类别：
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

项目摘要

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.

项目概要急性髓系白血病 (AML) 占儿童白血病病例的 20%。与急性淋巴母细胞相比白血病（ALL），AML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的毒性。与老年人的 AML 相比，儿童 AML 的全基因组研究，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。此外，虽然转录因子融合被假设为促进允许 AML 发展的转录特征，实验数据表明信号突变在驱动体内白血病生长中发挥着核心作用。因此，同时针对 AML中异常的转录程序和异常的信号通路是一种合理的治疗方法这对于儿童和 AYA 患者尤其重要。该提案的总体目标是研究有前途的药物组合的功效，同时针对儿科 AML 的关键途径并阐明药物的分子机制通过以下具体目标对这些有针对性的方法产生协同作用和抵制：(1) 确定和验证药物协同作用和对 BET + MEK 抑制的抵抗机制； (2) 调查该组合在儿童 AML 患者衍生异种移植 (PDX) 模型中的体内疗效。