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

项目总结 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 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 与治疗相关的毒性。与老年人的AML不同，对儿童AML的全基因组研究， 青少年和青壮年(Aya)表现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发展的转录签名，实验数据表明 信号突变在推动体内白血病增长方面发挥着核心作用。因此，同时针对 AML的转录程序异常和信号通路异常是一种合理的治疗方法 这与儿童和Aya患者尤其相关。 这项提案的总体目标是调查有希望的药物组合的有效性，这些药物组合 同时靶向儿童急性髓系白血病的关键通路并阐明药物的分子机制 通过以下具体目标协同和抵制这些有针对性的办法：(1)确定和 验证药物协同作用和对BET+MEK抑制耐药的机制；以及，(2)研究 这种组合在儿童急性髓细胞白血病患者来源异种移植(PDX)模型中的体内疗效。

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.