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.

恶性儿童高级别神经胶质瘤 (pHGG) 会浸润大脑并迅速生长，儿童癌症相关死亡的主要原因。迫切需要新的针对这些肿瘤的治疗。我们的研究团队和其他人已经确定了几个相关的 pHGG 中受体酪氨酸激酶 (RTK)（例如 MET、ALK 和 NTRK）的融合突变肿瘤细胞。这些突变异常地过度激活 RTK，导致 pHGG 癌症发生和进展。高达 40% 的 pHGG 肿瘤具有这些和类似的 RTK 融合。多项FDA- 已批准的特定酪氨酸激酶抑制剂 (TKI) 可以针对 RTK 突变 pHGG。然而，TKI 治疗不足以消除人类体内的肿瘤细胞。尽管来自小鼠模型的令人信服的数据。最近的研究表明，人类神经细胞类型，包括神经胶质细胞，表现出不同的发育特征、炎症反应和代谢特征，并且与相比表现出更大的发育异质性他们的小鼠对应物。我们预测这些差异可能是人类特异性的基础对 TKI 和其他 RTK 靶向疗法的适应，特别是在发育中的大脑中小儿癌症。为了检验我们的假设，我们的目标是 1) 使用以下方法创建 pHGG 类器官模型将人类患者来源的 pHGG 干细胞移植到人类 iPSC 来源的大脑类器官中近似出生后早期人类脑组织的培养物，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。希望通过我们的努力，开发出新的人性化 pHGG 实验模型并确定可引入的药物组合未来针对这种致命疾病的临床试验。