Human Organoid Models for Pediatric High-Grade Gliomas

儿童高级别胶质瘤的人体类器官模型

基本信息

批准号：
10727450
负责人：
Renee D Read
金额：
$ 43.04万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-11 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10727450
关键词：
Adopted Affect Animal Model Astrocytes Biological Biological Assay Brain Cancer Etiology Cell Culture Techniques Cells Central Nervous System Neoplasms Child Childhood Childhood Glioma Chimera organism Clinical Trials Coculture Techniques Complex Cytokine Signaling Data Development Disease Disease regression Drug Combinations Drug Screening Drug Targeting Drug Tolerance Drug resistance Engraftment Epidermal Growth Factor Receptor Experimental Models FDA approved Future Gene Expression Profiling Gene Fusion Genomics Glioma Goals H3 K27M mutation Heterogeneity Histones Human Image Infiltration Inflammatory Inflammatory Response Intervention Label Lesion Malignant - descriptor Malignant Childhood Neoplasm Malignant neoplasm of central nervous system Mediating Metabolic Modeling Mus Mutation Natural Immunity Neuroglia Neurons Organoids PDGFRB gene Patients Pharmaceutical Preparations Physiological Procedures Process Receptor Protein-Tyrosine Kinases Reporting Research Resistance Resistance development Signal Pathway Signal Transduction Study models Testing Therapeutic Toll-like receptors Tumor Stem Cells Tyrosine Kinase Inhibitor Variant antitumor drug brain tissue cancer initiation cell type childhood cancer mortality drug candidate drug testing engineered stem cells experimental study fetal improved induced pluripotent stem cell inhibitor therapy insight migration mosaic mouse model mutant neoplastic neoplastic cell nerve stem cell neural neurodevelopment novel therapeutic intervention pharmacologic postnatal postnatal human pre-clinical precision medicine progenitor response self-renewal single-cell RNA sequencing stem cell engraftment stem cells stem-like cell targeted treatment transcriptome sequencing treatment response tumor tumor progression

项目摘要

Malignant pediatric high-grade gliomas (pHGGs), which infiltrate the brain and grow rapidly, are a leading cause of cancer-related deaths in children. There is an urgent need for new treatments for these tumors. Our research team and others have identified several related fusion mutations in receptor tyrosine kinases (RTKs), such as MET, ALK, and NTRK, in pHGG tumor cells. These mutations abnormally hyperactivate RTKs to cause pHGG cancer initiation and progression. Up to 40% of pHGG tumors have these and similar RTK fusions. Several FDA- approved specific tyrosine kinase inhibitors (TKIs) exist that target RTK mutations found in pHGGs. However, treatment with TKIs is not sufficient to eliminate tumor cells in human patients, despite compelling data from mouse models. Recent research has shown that human neural cell types, including glia, display different developmental profiles, inflammatory responses, and metabolic features and show greater developmental heterogeneity compared to their murine counterparts. We predict that these differences may underlie human-specific adaptations to TKIs and other RTK targeted therapies, particularly in the developing brain in pediatric cancers. To test our hypothesis, we will Aim 1) create pHGG organoid models using human patient-derived pHGG stem cells engrafted into human iPSC-derived brain organoid cultures that approximate early postnatal human brain tissue, and Aim 2) model how interactions between pHGG cells and the human neural microenvironment affect responses to TKIs and other anti-tumor drugs. With our efforts, we hope to develop new humanized experimental models for pHGG and to identify drug combinations that may be brought into future clinical trials for this deadly disease.

恶性小儿高度神经胶质瘤（PHGGS），渗入大脑并迅速生长，是儿童与癌症相关的死亡的主要原因。迫切需要新的这些肿瘤的治疗方法。我们的研究团队和其他人已经确定了几个相关的 PHGG中的受体酪氨酸激酶（RTK）（例如Met，Alk和NTRK）中的融合突变肿瘤细胞。这些突变异常过度活化的RTK引起PHGG癌的启动和进展。多达40％的PHGG肿瘤具有这些和类似的RTK融合。几个FDA- 存在批准的特定酪氨酸激酶抑制剂（TKI），该靶向RTK突变 phggs。但是，用TKI的治疗不足以消除人类的肿瘤细胞尽管来自小鼠模型的数据令人信服，但患者。最近的研究表明人类神经细胞类型，包括神经胶质，表现出不同的发育特征，炎症反应和代谢特征，并显示出更大的发育异质性他们的鼠。我们预测这些差异可能是人类特异性的基础适应TKI和其他RTK靶向疗法，特别是在发育中的大脑中小儿癌。为了检验我们的假设，我们将目标1）使用人类患者衍生的PHGG干细胞植入了人IPSC衍生的脑器官中近似早期产后人脑组织的培养物，目标2）模拟如何 PHGG细胞与人类神经微环境之间的相互作用影响对 TKI和其他抗肿瘤药物。在我们的努力下，我们希望开发新的人性化 PHGG的实验模型并确定可能带入的药物组合这种致命疾病的未来临床试验。