Credentialing murine models for glioblastoma preclinical drug development

摘要 精确医学有望通过针对特定突变的药物来彻底改变肿瘤学。然而， 靶向药物在作为单一药物使用时未能产生持久的临床反应 胶质母细胞瘤(GBM)是最常见和最致命的原发脑肿瘤。转基因小鼠 (GEM)模型对于此类突变的功能验证是必不可少的，但技术限制 阻止了它们在临床前癌症药物开发中的广泛使用。米勒实验室已经研发出非 生殖系创业板(NGEM)模型。贝伦斯实验室已经进行了全面的基因组和 患者来源的人类异种移植的遗传多样性和忠实小组的化学排斥性分析 (PDX)型号。约翰逊实验室开发出一种新的化学蛋白质组学方法，即多重抑制物 珠-质联用(MIB-MS)评估细胞动态组En的激活状态 MASSE的研究表明，动态的动态组重新编程有助于靶向耐药。在这 多PI项目，我们将结合我们的专业知识来解决以下目标：(1)认证PDX模型 (2)建立基因匹配的NGEM模型。 不同的起源细胞；以及(3)通过动态动态组分析来验证PDX和NGEM模型。我们会 开发具有明确的驱动突变和细胞起源的NGEM模型的遗传多样性小组， 将是PDX的有用辅助药物，用于临床前药物开发。然后，我们将对PDX和NGEM进行认证 利用跨物种基因组、转录组和动态组对切除的GBM标本进行建模，以及 药物反应分析。模特将与人类同行进行基因匹配，并用于 开发合理的联合疗法，从基因组上对抗单一药物耐药机制- 明确的肿瘤亚型。因此，这项工作将有助于实现神经精确医学的前景- 肿瘤学。

ABSTRACT Precision medicine promises to revolutionize oncology by targeting drugs to specific mutations. However, targeted drugs have failed to produce durable clinical responses when used as single agents in glioblastoma (GBM), the most common and deadly primary brain tumor. Genetically engineered mouse (GEM) models are essential for functional validation of such mutations, but technical limitations have prevented their widespread use in preclinical cancer drug development. The Miller Lab has developed non- germline GEM (nGEM) models. The Berens Lab has performed comprehensive genomic and chemovulnerability profiling in a genetically diverse and faithful panel of patient-derived human xenograft (PDX) models. The Johnson Lab has developed a novel chemical proteomics method, multiplex inhibitor beads coupled with mass spectrometry (MIB-MS), to assess the activation state of the cellular kinome en masse and has shown that dynamic kinome reprogramming contributes to targeted drug resistance. In this Multi-PI project, we will combine our expertise to address the following Aims: (1) To credential PDX models against human GBM by kinome proteomics; (2) To develop genetically-matched nGEM models from distinct cells of origin; and (3) To credential PDX and nGEM models by dynamic kinome profiling. We will develop a genetically diverse panel of nGEM models with defined driver mutations and cellular origins that will be useful adjunct to PDX for preclinical drug development. We will then credential both PDX and nGEM models against resected GBM specimens using cross-species genome, transcriptome, and kinome, and drug response profiling. Models will be genomically matched to their human counterparts and used to develop rational combination therapies that combat single agent resistance mechanisms in genomically- defined tumor subtypes. This work will therefore help realize the promise of precision medicine in neuro- oncology.