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

项目摘要 表皮生长因子（EGFR）癌基因扩增并驱动55%的成年人肿瘤生长 胶质母细胞瘤（GBM）。然而，EGFR抑制剂未能证明GBM的临床益处， 这是神经肿瘤学领域面临的最根本的挑战之一。正如国家癌症中心所强调的那样， 研究所最近关于GBM进展的智囊团，尽管GBM的基因组基础有明确的信号， 包括EGFR扩增的高频率，新药开发计划已经停滞， 临床失败的高风险。肿瘤内的遗传异质性，以及许多肿瘤患者的脑-血浆比率差， 候选药物，被认为在临床失败中起主要作用。基于团队最近的发现 证明EGFR几乎仅在染色体外DNA颗粒（ecDNA）上扩增， 肿瘤内遗传异质性、加速的肿瘤演变和EGFR抑制剂抗性，以及它们的 发现EGFR扩增时产生的可操作的代谢依赖性，该提案将 鉴定EGFR扩增的GBM选择性依赖于其存活的蛋白质，即使在高度异质性的细胞中， 肿瘤的该建议将假设驱动的方法与使用基于活动的 蛋白质谱分析（ABPP）。在GBM的临床相关患者衍生模型中，该提议采用化学- 第一种发现EGFR扩增时产生的可操作依赖性和 与这些蛋白质结合，可以使其具有高度的脑渗透性。通过部署全功能化（FF） 小分子文库，以实现从表型筛选到活体靶向鉴定的直接进展 GBM细胞，包括EGFR扩增的患者来源的GBM，该提案有望为可操作的 用于患者体内的治疗靶点。拟议的综合办法提供了一条快速途径， 启动直接解决GBM基本挑战的新药开发。

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.