Human Organoid Models for Pediatric High-Grade Gliomas

儿童恶性高级别胶质瘤(PHGGs)侵袭大脑并迅速生长，是 这是导致儿童癌症相关死亡的主要原因。迫切需要新的 这些肿瘤的治疗。我们的研究团队和其他人发现了几个相关的 PHGG中受体酪氨酸激酶(RTK)的融合突变，如MET、ALK和NTRK 肿瘤细胞。这些突变异常地过度激活RTK导致PHGG癌症的发生 和进步。高达40%的PHGG肿瘤有这些和类似的RTK融合。几个FDA- 已批准的特定酪氨酸激酶抑制剂(TKI)存在靶向RTK突变 PHGGS。然而，TKIs的治疗不足以消除人体内的肿瘤细胞 患者，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，炎症性 反应和代谢特征，并显示出更大的发育异质性 它们的鼠类同行。我们预测，这些差异可能是人类特有的 适应TKIs和其他RTK靶向治疗，特别是在 儿科癌症。为了验证我们的假设，我们将1)创建PHGG有机体模型 人患者来源的PHGG干细胞植入人iPSC来源的脑有机体 接近出生后早期人脑组织的培养，以及目标是如何 PHGG细胞与人类神经微环境之间的相互作用影响对 TKIs和其他抗肿瘤药物。通过我们的努力，我们希望开发出新的人性化 PHGG的实验模型和识别可能引入的药物组合 未来对这种致命疾病的临床试验。

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.