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Targeting Childhood Brain Cancer in a Dish to Catalyze New Therapies

University of California, Davis Medical Center
Paul Knoepfler, PhD
Grant Type: 
Innovation Grants
Year Awarded: 
Type of Childhood Cancer: 
Project Description: 

Greater than 90% of children diagnosed with high-grade pediatric gliomas die within two years of diagnosis, even with today's best treatments. A desperate need exists for more effective therapies that are specifically designed for pediatric gliomas, which are different from adult gliomas. A factor called H3.3 was recently discovered to be frequently mutated in these tumors, making H3.3 an attractive new therapeutic target. 

Project Goal 
We propose to test the hypothesis that mutant H3.3 transforms normal brain stem cells into glioma and that we can target the mutations in preclinical studies using a powerful new technology we developed called “childhood cancer in a dish.”  In this way, we can grow miniature human brain-like structures called organoids in a dish. Strikingly, we can grow pediatric gliomas inside of these human mini-brains to study and test new drug treatments. In addition, we already used CRISPR gene-editing to revert H3.3 mutations back to the normal wildtype form in pediatric glioma cells and conversely introduced the H3.3 mutations in previously wildtype cells. We will study these gene-edited cells and test the effects of specific drugs on their cancer behavior in the mini-brain model. The proposed work will advance the understanding of childhood glioma and provide new ways to attack it. Our ultimate goal is a cure for childhood glioma via treatments that are more precise and molecularly targeted (versus systemic), less toxic and have higher efficacy.