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Credentialing next-generation human glioma models for precision therapeutics

认证下一代人类神经胶质瘤模型的精准治疗

基本信息

批准号：
10549346
负责人：
Frank Furnari
金额：
$ 55.6万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-12 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10549346
关键词：
Address Affect Alabama Biological Biological Models Biology Blood - brain barrier anatomy Brain Brain Neoplasms CDKN2A gene Cells Chemicals Clinic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Combined Modality Therapy Complex Coupled Credentialing Data Deletion Mutation Development Disease Drug Targeting Drug resistance Engineering Engraftment Ensure Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Extracellular Domain Failure Foundations Future Generations Genetic Genetic Engineering Genetic Heterogeneity Genomics Genotype Glioblastoma Glioma Goals Growth Heterogeneity Human Human Pathology Inflammatory Investigational Therapies Malignant Neoplasms Malignant neoplasm of brain Malignant neoplasm of lung Mass Spectrum Analysis Methods Missense Mutation Modeling Molecular Molecular Conformation Molecular and Cellular Biology Mutation Operative Surgical Procedures Organoids PIK3CG gene PTEN gene Pathway interactions Patient Selection Patients Penetrance Pharmaceutical Preparations Pharmacotherapy Phenotype Phosphotransferases Pre-Clinical Model Precision therapeutics Preclinical Drug Development Primary Brain Neoplasms Proteomics Publishing Receptor Protein-Tyrosine Kinases Signal Transduction Symbiosis Testing Therapeutic Therapeutic Uses Tyrosine Kinase Inhibitor Universities Work Xenograft procedure combat combinatorial design driver mutation drug sensitivity epidermal growth factor receptor VIII epigenomics established cell line experience experimental study genome editing human disease human model induced pluripotent stem cell inhibitor inhibitor therapy mouse model mutant neoplastic cell nerve stem cell neuro-oncology next generation next generation sequencing novel overexpression patient derived xenograft model preclinical development preservation resistance mechanism response small molecule success transcriptomics tumor tumor heterogeneity tumorigenesis

项目摘要

ABSTRACT Despite notable success in EGFR-driven lung cancer, precision therapeutics have failed in EGFR-driven gliomas, the most common and deadly primary brain tumors. Reasons for failure of EGFR therapies in this clinical context include the lack of preclinical models that faithfully recapitulate the biology of EGFR-driven gliomas, including intra-tumor heterogeneity, drugs specifically designed to target invasive brain tumor cells located behind and intact blood-brain barrier (BBB), and adaptive drug resistance. Here we will develop and molecularly credential novel, EGFR-driven human glioma models for use in preclinical development of EGFR tyrosine kinase inhibitor (TKI)-based therapies. The foundation of the proposal comes from the Furnari Lab, who developed a novel platform (iGBM) for engineering glioma models using CRISPR genome editing and has established intra-tumor genetic heterogeneity as a symbiotic driver of tumorigenesis. The Miller Lab has extensive experience in small molecule experimental therapeutics using genetically engineered gliomas model and next-generation sequencing. He also used a novel chemical proteomics method, multiplex inhibitor beads coupled with mass spectrometry, to assess the glioma kinome en masse and showed that dynamic kinome reprogramming contributes to targeted drug resistance in glioma models. He is now at the University of Alabama at Birmingham, where local collaborators have extensive experience with biologically faithful human patient-derived xenograft (PDX) models. The O’Rourke Lab is a pioneer in development of sophisticated glioblastoma organoid (GBO) models that faithfully recapitulate the biology of molecularly and cellularly heterogeneous human tumors. In this Multi-PI project, we will combine our expertise to address the following Aims: (1) To develop novel genetically engineered human models driven by the most common EGFR extracellular domain mutations. We will then biologically and molecularly credential these models against genetically-matched PDX and GBO using genomics, epigenomics, transcriptomics, and kinome proteomics, and therapeutically challenge them using a panel of EGFR TKI, including one designed to specifically target invasive glioma cells behind the intact BBB. (2) To credential heterogeneous EGFR mutant iGBM models via biological, molecular, and EGFR TKI therapeutic profiling. We will thus develop human models with defined driver mutations that will be useful adjuncts to PDX/GBO for preclinical drug development. Models will be used to develop future rational combination therapies that combat drug resistance and enhance EGFR TKI efficacy. This work will therefore help realize the unmet need of precision therapeutics in neuro-oncology.

抽象的尽管在 EGFR 驱动的肺癌中取得了显着的成功，但精准治疗在 EGFR 驱动的肺癌中却失败了神经胶质瘤，最常见和致命的原发性脑肿瘤。 EGFR治疗失败的原因临床背景包括缺乏忠实概括 EGFR 驱动生物学的临床前模型神经胶质瘤，包括肿瘤内异质性，专门设计用于靶向侵袭性脑肿瘤细胞的药物位于完整的血脑屏障（BBB）后面，并且具有适应性耐药性。在这里我们将开发以及分子证明新颖的、EGFR驱动的人类神经胶质瘤模型，用于临床前开发基于 EGFR 酪氨酸激酶抑制剂 (TKI) 的疗法。该提案的基础来自于 Furnari Lab，开发了一个使用 CRISPR 设计神经胶质瘤模型的新型平台 (iGBM) 基因组编辑并建立了肿瘤内遗传异质性作为共生驱动因素肿瘤发生。米勒实验室在小分子实验疗法方面拥有丰富的经验基因工程神经胶质瘤模型和下一代测序。他还使用了一种新型化学物质蛋白质组学方法，多重抑制剂珠与质谱联用，评估神经胶质瘤 kinome en Masse 并表明动态激酶组重编程有助于靶向耐药性在神经胶质瘤模型中。他现在在阿拉巴马大学伯明翰分校，当地的合作者已经在生物学上忠实的人类患者来源的异种移植（PDX）模型方面拥有丰富的经验。这 O’Rourke 实验室是开发复杂胶质母细胞瘤类器官 (GBO) 模型的先驱，该模型忠实地概括了分子和细胞异质人类肿瘤的生物学。在这个多PI 项目中，我们将结合我们的专业知识来实现以下目标：（1）开发新的基因由最常见的 EGFR 胞外域突变驱动的工程人体模型。我们随后将使用这些模型在生物学和分子水平上针对基因匹配的 PDX 和 GBO 进行验证基因组学、表观基因组学、转录组学和激酶组蛋白质组学，并使用它们进行治疗性挑战一组 EGFR TKI，其中包括专门针对完整神经胶质瘤背后的侵袭性神经胶质瘤细胞设计的 BBB。 (2) 通过生物学、分子学和EGFR来验证异质EGFR突变体iGBM模型 TKI 治疗分析。因此，我们将开发具有明确驱动突变的人类模型，这些突变将用于临床前药物开发的 PDX/GBO 的有用辅助剂。模型将用于开发未来合理的联合疗法可对抗耐药性并增强 EGFR TKI 疗效。这项工作将因此有助于实现神经肿瘤学中精准治疗尚未得到满足的需求。