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。

基本信息

批准号：
10436295
负责人：
BENJAMIN F CRAVATT
金额：
$ 67.19万
依托单位：
STANFORD UNIVERSITY
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：
2021-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10436295
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 member neuro-oncology novel novel therapeutics overexpression particle screening small molecule libraries therapeutic target tumor tumor growth

项目摘要

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.

项目概要表皮生长因子 (EGFR) 癌基因被扩增并驱动 55% 成年人的肿瘤生长然而，EGFR 抑制剂未能证明对胶质母细胞瘤 (GBM) 具有临床益处。正如国家癌症研究所强调的那样，这是神经肿瘤学领域面临的最基本的挑战之一。尽管关于 GBM 基因组基础的明确信号，研究所最近关于 GBM 进展的智囊团，包括EGFR扩增频率高，新药开发计划因以下原因而陷入停滞临床失败的高风险，以及许多肿瘤的脑浆比较差。基于该团队最近的发现，候选药物被认为在临床失败中发挥着重要作用。证明 EGFR 几乎完全在染色体外 DNA 颗粒 (ecDNA) 上扩增，从而驱动肿瘤内遗传异质性、加速肿瘤进化和 EGFR 抑制剂耐药性及其发现当 EGFR 扩增时出现可操作的代谢依赖性，该提案将识别 EGFR 扩增的 GBM 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该提案将假设驱动的方法与基于活动的公正发现相结合。在临床相关的 GBM 患者衍生模型中，该提案采用了化学- 第一种方法来发现 EGFR 扩增时产生的可操作依赖性和配体通过部署全功能化（FF），可以使这些蛋白质具有高度的大脑渗透性。小分子文库可实现从表型筛选到活体靶点鉴定的直接进展 GBM 细胞，包括来自患者的具有扩增 EGFR 的 GBM，该提案有望为可采取行动提供信息所提出的综合方法为患者的体内治疗靶点提供了一条快速途径。启动新药开发，直接解决 GBM 的根本挑战。