Human Organoid Models for Pediatric High-Grade Gliomas

儿童高级别胶质瘤的人体类器官模型

• 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
• 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

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.

恶性小儿高级别胶质瘤（pHGG），浸润大脑并迅速生长， 是儿童癌症相关死亡的主要原因。迫切需要新的 治疗这些肿瘤。我们的研究小组和其他人已经确定了几个相关的 pHGG中受体酪氨酸激酶（RTK）如MET、ALK和NTRK的融合突变 肿瘤细胞这些突变异常过度激活RTK，导致pHGG癌症启动 和进步。高达40%的pHGG肿瘤具有这些和类似的RTK融合。几个FDA- 存在批准的特异性酪氨酸激酶抑制剂（TKI），其靶向在以下中发现的RTK突变： pHGG。然而，用TKI治疗不足以消除人类中的肿瘤细胞。 尽管小鼠模型的数据令人信服。最近的研究表明，人类 神经细胞类型，包括神经胶质，显示不同的发育概况，炎性 反应和代谢特征，并显示出更大的发育异质性相比， 它们的鼠对应物。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靶向治疗的适应，特别是在发育中的大脑中， 儿科癌症为了验证我们的假设，我们将目标1）使用以下方法创建pHGG类器官模型： 植入人iPSC衍生的脑类器官中的人患者衍生的pHGG干细胞 培养近似于出生后早期人类脑组织的细胞，Aim 2）模拟了 pHGG细胞和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。通过我们的努力，我们希望开发新的人性化的 pHGG的实验模型，并确定可能被引入的药物组合， 这种致命疾病的未来临床试验