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 髓母细胞瘤是一组特别具有破坏性的儿童脑肿瘤，表现为 尽管接受了标准的护理治疗，但耐药性和持续进展。我们的临床前工作[1]确定 贝塔-溴域抑制剂作为治疗儿童髓母细胞瘤的一种有潜力的新药 (MB)和其他由MYC驱动的癌症，为在临床试验中评估这些药物提供了理论基础。然而， 单独使用BET抑制剂(Beti)治疗不太可能足以治愈，因为大多数肿瘤演变为 获得对单剂靶向治疗的抵抗力。克服治疗阻力的一个有吸引力的策略 是识别和利用耐药细胞中存在的新漏洞。代谢途径是特殊的。 在这方面的兴趣，因为它们通常依赖于几个必要的酶，经常在癌细胞中重新连接，而不是 正常细胞，支持和驱动适应性耐药，提供必要的生存能力，并可以 很容易被药物抑制剂靶向[3]。我们之前的工作应用了一种综合基因组学方法来 确定在MB中介导Beti反应的基因和途径[2]。这些研究表明，由MYC驱动的MB 对Beti具有获得性抗药性的细胞恢复被药物抑制的必要基因的转录，并显示 药物敏感细胞中不存在的细胞状态变化和新的脆弱性。我们现在有了一个不断增长的身体 有证据表明，抑制BET可下调关键脂代谢基因和 与代谢相关的信号通路，以及对Beti具有适应性抗性的MB细胞 表达并表现出对特定脂类代谢基因和转录调控因子的优先依赖性。 这些发现让我假设新陈代谢重新编程会在Beti药物中产生新的脆弱性- 耐受的MB细胞，可以靶向克服耐药性。这里描述的研究将表征 Beti耐药MB细胞脂代谢的改变，评估Beti驱动的代谢重排对 细胞信号和耐药表型，并探讨利用脂代谢的可能性 依赖作为一种新的方法来克服对Beti靶向治疗的耐药性。