Human Organoid Models for Pediatric High-Grade Gliomas

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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.