Integrated ligand and target discovery by chemical proteomics for glioblastoma treatment.

通过化学蛋白质组学整合配体和靶点发现用于胶质母细胞瘤治疗。

• 批准号: 10211553
• 负责人: BENJAMIN F CRAVATT
• 金额: $ 69.66万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10211553
• 关键词: Address; Adult Glioblastoma; American Association of Cancer Research; Astrocytes; Automobile Driving; Award; Biochemical; Biology; Brain; Caring; Cell membrane; Cells; Chemicals; Chemistry; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Dependence; Development; Epidermal Growth Factor; Evolution; Failure; Frequencies; Genes; Genetic Heterogeneity; Genomics; Glioblastoma; Growth; Growth Factor; Growth Factor Oncogenes; Heterogeneity; Human; In Vitro; Libraries; Ligands; Lipid Synthesis Pathway; Malignant Neoplasms; Malignant neoplasm of brain; Medical; Membrane Lipids; Metabolic; Methods; Modeling; Molecular; Molecular Biology; Molecular Target; National Cancer Institute; Patients; Pharmaceutical Chemistry; Pharmacology; Pharmacopoeias; Phenotype; Plasma; Play; Positioning Attribute; Program Development; Protein Inhibition; Proteins; Proteomics; Resistance; Role; Route; Signal Transduction; Stereotyping; Structure; Technology; Thinness; Validation; Work; activity-based protein profiling; cancer type; clinical risk; clinically relevant; drug candidate; drug development; effective therapy; experimental study; extrachromosomal DNA; high risk; in vivo; induced pluripotent stem cell; inhibitor/antagonist; member; neuro-oncology; novel; novel therapeutics; overexpression; particle; screening; small molecule libraries; therapeutic target; tumor; tumor growth

PROJECT SUMMARY The epidermal growth factor (EGFR) oncogene is amplified and drives tumor growth in 55% of adult glioblastomas (GBMs). However, EGFR inhibitors have failed to demonstrate clinical benefit in GBM, presenting one of the most fundamental challenges facing the field of neuro-oncology. As highlighted by the National Cancer Institute’s recent think tank on progress in GBM, despite clear signals about the genomic underpinnings of GBM, including the high frequency of EGFR amplification, new drug development programs have stalled because of the high risk of clinical failures. Intra-tumoral genetic heterogeneity, and the poor brain-plasma ratios of many drug candidates, are thought to play a major role in clinical failure. Building on the team’s recent discoveries demonstrating that EGFR is amplified almost exclusively on extrachromosomal DNA particles (ecDNA), driving intra-tumoral genetic heterogeneity, accelerated tumor evolution, and EGFR inhibitor resistance, and their discovery of actionable metabolic dependencies that arise when EGFR becomes amplified, this proposal will identify proteins on which EGFR-amplified GBMs selectively depend for survival, even in highly heterogeneous tumors. This proposal integrates a hypothesis-driven approach with unbiased discovery using activity-based protein profiling (ABPP). In clinically relevant patient-derived models of GBM, this proposal takes a chemistry- first approach to discover both actionable dependencies that arise when EGFR is amplified and ligands that engage these proteins, which can be made to be highly brain-penetrant. By deploying fully functionalized (FF) small-molecule libraries to enable direct progression from phenotypic screening to target identification in living GBM cells, including in patient-derived GBMs with amplified EGFR, this proposal is poised to inform actionable therapeutic targets for patients in vivo. The proposed integrated approach provides a rapid route towards initiating new drug development that directly addresses the fundamental challenges of GBM.

项目总结 表皮生长因子(EGFR)癌基因被扩增，并在55%的成年人中驱动肿瘤生长 胶质母细胞瘤(GBM)。然而，EGFR抑制剂未能证明在GBM中的临床益处，目前 神经肿瘤学领域面临的最根本的挑战之一。正如《国家癌症》杂志所强调的那样 研究所最近关于GBM进展的智囊团，尽管关于GBM的基因组基础有明确的信号， 包括高频率的EGFR扩增，新药开发计划因为 临床失败的高风险。肿瘤内遗传异质性，以及许多人的脑浆比例较低 候选药物，被认为是临床失败的主要原因。建立在团队最新发现的基础上 证明EGFR几乎只在染色体外DNA颗粒(EcDNA)上扩增，驱动 肿瘤内遗传异质性、肿瘤进展加速和EGFR抑制剂耐药性及其 当EGFR被放大时，发现可操作的代谢依赖，这一提议将 识别EGFR扩增的基底膜选择性依赖的蛋白质，即使在高度异质性的情况下也是如此 肿瘤。该建议将假设驱动的方法与基于活动的无偏见发现相结合 蛋白质图谱(ABPP)。在临床相关的患者衍生的GBM模型中，这一提议需要一种化学- 第一种方法，发现当EGFR被扩增时产生的可操作依赖关系和 让这些蛋白质参与进来，这些蛋白质可以被制成高度穿透大脑的物质。通过部署完全功能化(FF) 小分子文库使生物从表型筛选到靶标识别的直接进展 GBM细胞，包括具有扩增的EGFR的患者来源的GBM，这一提议有望告知可操作 活体患者的治疗靶点。拟议的综合方法提供了一条快速的途径， 启动新药开发，直接应对GBM的根本挑战。