American Association for Cancer Research
cd-23-0004_supplementary_table_6_suppst4.xlsx (12.4 kB)

Supplementary Table 6 from A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities

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posted on 2024-03-01, 15:40 authored by Michael McNicholas, Antonella De Cola, Zahedeh Bashardanesh, Amelia Foss, Cameron B. Lloyd, Steven Hébert, Damien Faury, Augusto Faria Andrade, Nada Jabado, Claudia L. Kleinman, Manav Pathania

ssGEA signatures derived from snRNA-seq data.


Canadian Institutes of Health Research (IRSC)

National Institutes of Health (NIH)

We Love You Connie Foundation

Poppies for Irini Foundation

Kat D Strong Foundation

Fonds de Recherche du Quebec-Sante

Natural Sciences and Engineering Research Council of Canada (NSERC)

Compute Canada and Calcul Quebec

Emily Parsons Foundation

Cancer Research UK (CRUK)

Brain Research UK (BRUK)

Great Ormond Street Hospital Charity (GOSH)

Genome Canada (GC)

Fondation Charles-Bruneau (Charles Bruneau Foundation)



Pediatric high-grade gliomas (pHGG) are lethal, incurable brain tumors frequently driven by clonal mutations in histone genes. They often harbor a range of additional genetic alterations that correlate with different ages, anatomic locations, and tumor subtypes. We developed models representing 16 pHGG subtypes driven by different combinations of alterations targeted to specific brain regions. Tumors developed with varying latencies and cell lines derived from these models engrafted in syngeneic, immunocompetent mice with high penetrance. Targeted drug screening revealed unexpected selective vulnerabilities—H3.3G34R/PDGFRAC235Y to FGFR inhibition, H3.3K27M/PDGFRAWT to PDGFRA inhibition, and H3.3K27M/PDGFRAWT and H3.3K27M/PPM1DΔC/PIK3CAE545K to combined inhibition of MEK and PIK3CA. Moreover, H3.3K27M tumors with PIK3CA, NF1, and FGFR1 mutations were more invasive and harbored distinct additional phenotypes, such as exophytic spread, cranial nerve invasion, and spinal dissemination. Collectively, these models reveal that different partner alterations produce distinct effects on pHGG cellular composition, latency, invasiveness, and treatment sensitivity. Histone-mutant pediatric gliomas are a highly heterogeneous tumor entity. Different histone mutations correlate with different ages of onset, survival outcomes, brain regions, and partner alterations. We have developed models of histone-mutant gliomas that reflect this anatomic and genetic heterogeneity and provide evidence of subtype-specific biology and therapeutic targeting.See related commentary by Lubanszky and Hawkins, p. 1516.This article is highlighted in the In This Issue feature, p. 1501

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