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：
10652580
负责人：
BENJAMIN F CRAVATT
金额：
$ 66.69万
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/10652580
关键词：
Acceleration 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 Pharmacopoeias Phenotype Plasma Play Positioning Attribute Program Development Proteins Proteomics Resistance Role Route Signal Transduction Stereotyping Structure Technology Thinness Validation Work Writing activity-based protein profiling cancer type chemoproteomics 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 pharmacologic 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.

项目摘要表皮生长因子（EGFR）癌基因被放大，并驱动55％的成人肿瘤生长胶质母细胞瘤（GBMS）。但是，EGFR抑制剂未能证明GBM的临床益处神经肿瘤学领域面临的最根本挑战之一。正如国家癌症所强调的那样研究所最近关于GBM进展的智囊团，目的地明确有关GBM基因组基础的信号，包括EGFR扩增的高频率，由于临床失败的高风险。肿瘤内遗传异质性和许多许多人的脑质量比率候选药物被认为在临床衰竭中起着重要作用。建立在团队最近的发现的基础上证明eGFR几乎仅在牙外DNA颗粒（ECDNA）上放大，驱动肿瘤内遗传异质性，加速肿瘤进化和EGFR抑制剂及其抗性发现EGFR放大时会发现可行的代谢依赖性，该建议将识别蛋白质在哪些EGFR放大的GBM选择性地依赖生存，即使在高度异质性中也是如此肿瘤。该提案将假设驱动的方法与基于活动基于活动的无偏见集成蛋白质分析（ABPP）。在临床相关的GBM患者衍生模型中，该建议采用化学 - 发现EGFR放大时出现的两个可行依赖性和配体的第一种方法参与这些蛋白质，可以使这些蛋白质成为高度脑渗透剂。通过部署功能齐全（FF）小分子库可以直接从表型筛选到生活中的目标识别 GBM细胞，包括具有扩增EGFR的患者衍生的GBM，该提案被毒死以告知可操作的体内患者的治疗靶标。拟议的集成方法为快速迈进了启动直接应对GBM的基本挑战的新药物开发。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A Cell Type Selective YM155 Prodrug Targets Receptor-Interacting Protein Kinase 2 to Induce Brain Cancer Cell Death.

细胞类型选择性 YM155 前药以受体相互作用蛋白激酶 2 为靶点，诱导脑癌细胞死亡。

DOI：
10.1021/jacs.2c11715
发表时间：
2023
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
West,ThomasJ;Bi,Junfeng;Martínez-Peña,Francisco;Curtis,EllisJ;Gazaniga,NathaliaR;Mischel,PaulS;Lairson,LukeL
通讯作者：
Lairson,LukeL

Activity-based protein profiling - finding general solutions to specific problems.

基于活性的蛋白质分析 - 寻找特定问题的通用解决方案。