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

项目总结/摘要 MYC驱动的髓母细胞瘤是一组特别具有破坏性的儿童脑肿瘤， 耐药性和持续进展，尽管标准护理治疗。我们的临床前工作[1]确定了 BET-溴结构域抑制剂作为治疗儿童髓母细胞瘤的潜在有前途的新一类药物 (MB)以及其他MYC驱动的癌症，为在临床试验中评估这些药物提供了依据。然而，在这方面， 单独用BET抑制剂（BETi）治疗不太可能足以治愈，大多数肿瘤发展为 获得对单药靶向治疗的耐药性。克服治疗抵抗的有吸引力的策略 是识别和利用耐药细胞中存在的新弱点。代谢途径是特别的 在这种情况下，由于它们通常依赖于很少的必需酶，因此它们经常在癌细胞中“重新连接”， 正常细胞，支持和驱动适应性耐药性药物，提供必要的生存能力，并可以 容易被药理学抑制剂靶向[3]。我们以前的工作应用了整合基因组学方法， 鉴定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 具有对BETi的获得性抗性的细胞恢复被药物抑制的必需基因的转录， 细胞状态的变化和药物敏感细胞中不存在的新弱点。我们现在有一个不断增长的身体 有证据表明BET抑制下调关键脂质代谢基因的表达， 代谢相关的信号通路，并且MB细胞对BETi的适应性抗性差异 表达并表现出对特定脂质代谢基因和转录调节因子的优先依赖性。 这些发现使我假设代谢重编程在BETi药物中产生了新的漏洞- 耐受性MB细胞可以靶向克服耐药性。本文描述的研究将表征 BETi抗性MB细胞的脂质代谢改变，评估BETi驱动的代谢重新布线对 细胞信号传导和抗性表型，并探讨利用脂质代谢的可能性 依赖性作为克服对BETi靶向治疗的抗性的新方法。

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.