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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

基本信息

批准号：
10375386
负责人：
Leslie Lupien
金额：
$ 6.75万
依托单位：
DANA-FARBER CANCER INST
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：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375386
关键词：
Acetyl Coenzyme A Address Anticholesteremic Agents Binding Proteins Binding Sites Bromodomain 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 Pharmacology Phenotype Proteins Proteolysis RNA Regulatory Element Research Resistance SP1 gene Saturated Fatty Acids Signal Pathway Signal Transduction Stearoyl-CoA Desaturase Sterols Testing Therapeutic Up-Regulation Western Blotting Work activating transcription factor cancer cell cholesterol biosynthesis chromatin immunoprecipitation desaturase differential expression drug-sensitive efficacy evaluation electron donor farnesyltranstransferase in vivo in vivo Model inhibitor inhibitor therapy interest isoprenoid isoprenylation knock-down lipid metabolism lipidomics medulloblastoma medulloblastoma cell line metabolic phenotype mevalonate novel novel drug class novel strategies overexpression 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

项目摘要

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.

项目总结/文摘