Exploiting the Differentiation Potential of Pediatric High-Grade Glioma to Discover Novel Therapeutic Opportunities
Lay Summary: Brain tumors are the number one cause of cancer-related death in children. High-grade gliomas of the brain stem and hemispheres are the most lethal pediatric brain tumors: Most children succumb to their disease within 1-3 years after diagnosis. Within a child’s developing brain, rapidly dividing stem cells exit the cell cycle and differentiate into non-replicating neurons and glia. In preliminary studies, I applied a technique called single-cell RNA-sequencing to thousands of individual pediatric high-grade glioma cells. My studies showed that these tumors are mostly composed of quickly dividing cells that resemble normal replicating stem cells. However, I also discovered that some cancer cells are able to differentiate towards normal brain cells. These cells stop dividing and lose their potential to form new tumors despite having the same mutations as immature, dividing high-grade glioma cells. This observation suggests that differentiation therapy, which has been successful in treating other childhood cancers like acute promyelocytic leukemia, could work in pediatric high-grade gliomas and lead to better responses than current cytotoxic chemotherapy regimens with limited benefit.
Project Goal: To test this hypothesis, I will use a method called CRISPR-gene editing to ablate specific genes that I have identified as potential antagonists of the developmental programs in both brainstem and hemispheric high-grade gliomas. I predict that the ablation of these genes will lead to cell cycle exit and growth arrest of glioma cells. My study plan may identify novel targets for high-grade glioma drug development and lay the foundation for new treatment strategies in this deadly disease.
Project Update 2024: Our paper "GABAergic neuronal lineage development determines clinically actionable targets in diffuse hemispheric glioma, H3G34-mutant" was just published in Cancer Cell. This study would have not been possible without getting the A-award! In short, we describe here how cells in this special group of high-grade gliomas, called H3G34-mutant Diffuse Hemispheric Glioma, can differentiate towards astrocytes (as all other gliomas), but also towards GABAergic neuron-like cells. Tumor cells not only begin to resemble GABAergic neurons, they also start producing the neurotransmitter GABA, and form little "nests" of cells that mirror normal development of GABAergic neurons. This is interesting and will be followed by many exciting cancer neuroscience studies, but also presents a new way to target these tumors in particular. When combining these findings with a functional CRISPR screen in patient-derived cell lines, we found that tumor cells depend on the continued expression of neuronal progenitor marker genes. In addition, they rely on the proper function of CDK6 to keep their proliferation, as not all of them differentiate into GABAergic neuron-like cells. We found that genetically deleting or chemically inhibiting CDK6 makes cells differentiate more and grow less. Mice with these tumors, as well as our first patient treated with CDK6 inhibitor Ribociclib (after two other treatments had failed) survived much longer than expected.
