Lipid metabolism as a therapeutic vulnerability in BET inhibitor-resistant medulloblastoma

脂质代谢作为 BET 抑制剂耐药性髓母细胞瘤的治疗脆弱性

• 批准号: 10608123
• 负责人: Leslie Lupien
• 金额: $ 7.18万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10608123
• 关键词: Acetyl Coenzyme A; Anticholesteremic Agents; Binding Proteins; Binding Sites; Bromodomain; Bromodomains and extra-terminal domain inhibitor; CRISPR/Cas technology; Cell Cycle Progression; Cells; Characteristics; Child; Childhood Brain Neoplasm; Cholesterol; Cholesterol Homeostasis; Clinical Trials; Combined Modality Therapy; Complex; Cytochromes; DNA; Data; Dependence; Drug Tolerance; Drug resistance; Enzymes; Essential Genes; Event; Exhibits; Family; Genes; Genetic; Genetic Transcription; Genomic approach; Guanosine Triphosphate Phosphohydrolases; Helix-Turn-Helix Motifs; In Vitro; Leucine Zippers; Link; Lipids; Malignant Neoplasms; Mediating; Membrane Fluidity; Metabolic; Metabolic Pathway; Metabolism; Modeling; Monounsaturated Fatty Acids; NADP; Normal Cell; Oleic Acids; Oncogenic; Pathway interactions; Pharmaceutical Preparations; Phenotype; Proliferating; Proteins; Proteolysis; RNA; Regulatory Element; Research; Resistance; SP1 gene; SRE-1 binding protein; Saturated Fatty Acids; Signal Pathway; Signal Transduction; Stearoyl-CoA Desaturase; Sterols; Testing; Therapeutic; Up-Regulation; Western Blotting; Work; cancer cell; cholesterol biosynthesis; chromatin immunoprecipitation; desaturase; differential expression; drug-sensitive; efficacy evaluation; electron donor; farnesyltranstransferase; in vivo; in vivo Model; inhibitor; interest; isoprenoid; isoprenylation; knock-down; lipid metabolism; lipidomics; medulloblastoma; medulloblastoma cell line; metabolic phenotype; mevalonate; novel; novel drug class; novel strategies; overexpression; pharmacologic; pre-clinical; programs; protein transport; response; rho; small hairpin RNA; standard of care; targeted agent; targeted treatment; therapeutic target; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor metabolism; uptake

Project Summary/Abstract MYC-driven medulloblastomas are a particularly devastating group of pediatric brain tumors that exhibit resistance and continued progression despite standard of care treatments. Our preclinical work[1] identified BET-bromodomain inhibitors as a potentially promising new class of drugs for children with medulloblastoma (MB) and other MYC-driven cancers, providing rationale to evaluate these agents in clinical trials. However, treatment with BET inhibitor (BETi) alone is unlikely to be sufficient for a cure, with most tumors evolving to acquire resistance to single-agent targeted therapies. An attractive strategy to overcoming therapy resistance is to identify and exploit new vulnerabilities that exist in drug-tolerant cells. Metabolic pathways are of particular interest in this context as they often rely on few essential enzymes, are frequently “rewired” in cancer cells vs. normal cells, support and drive adaptive resistance to drug, provide essential survival capabilities, and can be easily targeted with pharmacologic inhibitors[3]. Our previous work applied an integrative genomics approach to identify genes and pathways mediating BETi response in MB[2]. These studies revealed that MYC-driven MB cells with acquired resistance to BETi reinstate transcription of essential genes suppressed by drug and exhibit changes in cell-state and new vulnerabilities not present in drug-sensitive cells. We now have a growing body of evidence showing that BET inhibition downregulates the expression of key lipid metabolism genes and metabolism-related signaling pathways, and that MB cells with adaptive resistance to BETi differentially express and exhibit preferential dependency on specific lipid metabolic genes and transcriptional regulators. These findings led me to hypothesize that metabolic reprogramming creates novel vulnerabilities in BETi drug- tolerant MB cells that can be targeted to overcome resistance. The studies described herein will characterize the altered lipid metabolism of BETi-resistant MB cells, assess the impact of BETi-driven metabolic rewiring on cell signaling and the resistance phenotype, and investigate the possibility of exploiting lipid metabolic dependencies as a novel approach to overcome resistance to BETi-targeted therapy.

项目摘要/摘要 MYC驱动的髓母细胞瘤是一组特别毁灭性的儿科脑肿瘤 阻力和持续进展目的地护理治疗标准。我们确定的临床前工作[1] BET-溴结构域抑制剂是髓母细胞瘤儿童的潜在有前途的新药物 （MB）和其他由MYC驱动的癌症，提供了在临床试验中评估这些药物的理由。然而， 仅使用BET抑制剂（BETI）治疗就不足以治愈，大多数肿瘤都会发展为 获得对单药靶向疗法的抵抗力。克服治疗抗性的有吸引力的策略 是识别和利用耐药细胞中存在的新漏洞。代谢途径特别 在这种情况下，人们的兴趣通常依赖于很少的基本酶，在癌细胞与癌细胞中经常“重新连接”。 正常细胞，支持和驱动对药物的适应性抗性，提供必不可少的生存能力，并且可以是 很容易用药物学抑制剂靶向[3]。我们以前的工作将综合基因组学方法应用于 确定MB中介导BETI反应的基因和途径[2]。这些研究表明，MYC驱动的MB 对BETI的耐药性的细胞恢复了被药物抑制的必需基因的转录 药物敏感细胞中不存在细胞状态和新漏洞的变化。我们现在的身体增长 证据表明，抑制下注降低了关键脂质代谢基因的表达和 代谢相关的信号通路，并且具有自适应抗BETI的MB细胞差异化 表达和表现出对特定脂质代谢基因和转录调节剂的优先依赖性。 这些发现使我假设代谢重编程在Beti药物中产生了新的脆弱性 - 可以针对克服抗性的耐受性MB细胞。本文描述的研究将表征 抗Beti耐药的MB细胞的脂质代谢改变了，评估了Beti驱动的代谢重新布线对 细胞信号传导和电阻表型，并研究利用脂质代谢的可能性 依赖性是一种克服对贝蒂靶向疗法的抵抗力的新方法。