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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.

Update - June 2020

Our ALSF-funded work has progressed well in the first year. We have more fully validated our panel of control and CRISPR-modified human cells, including both H3.3 wild-type cells and cells bearing histone H3.3 mutations. We have also extensively studied these cells to understand the mechanisms by which mutant H3.3 contributes to childhood high-grade gliomas. Our studies point to specific effects of different mutant forms of H3.3 protein on cells including changes in cell biology, epigenetics, and expression of specific genes and proteins. Interestingly, some changes in the cells are specific to the K27M mutant form of H3.3, while others are distinctly found in cells with the G34R mutation. However, overall, another notable finding is just how similar these mutations seem to be in how they affect cells. Our work so far also suggests that some of the mutant H3.3-related changes in cells could constitute novel therapeutic targets that could be the basis for new, more effective treatments in the future. Toward that goal, during the past year, we've also begun studies testing different drugs on our panel of cells, finding encouraging results for certain types of cells. In addition, we have conducted mouse xenograft studies that have generated some important data related to how mutant H3.3 alters tumor-related functions in vivo. Together, the work and data from year one form a strong foundation for the planned year 2 studies.