Reference Detail

Ref Type

Journal Article

PMID

(37011011)

Authors

McNicholas M, De Cola A, Bashardanesh Z, Foss A, Lloyd CB, Hébert S, Faury D, Andrade AF, Jabado N, Kleinman CL, Pathania M

Title

A Compendium of Syngeneic, Transplantable Pediatric High-Grade Glioma Models Reveals Subtype-Specific Therapeutic Vulnerabilities.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	13	7	2023 Jul 07	1592-1615	Cancer Discov

URL

Abstract Text

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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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA E545K	diffuse midline glioma, H3 K27M-mutant	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mekinist (trametinib) inhibited viability of mouse glioma cells expressing H3.1 K28M (reported as H3.1 K27M), ACVR1 G328V, and PIK3CA E545K in culture (PMID: 37011011).	37011011
FGFR1 N546K	diffuse midline glioma, H3 K27M-mutant	sensitive	Infigratinib	Preclinical - Cell culture	Actionable	In a preclinical study, Truseltiq (infigratinib) inhibited viability of mouse glioma cells expressing H3.3 K28M (reported as H3.3 K27M) and FGFR1 N546K (reported as N457K) in culture (PMID: 37011011).	37011011
FGFR1 N546K	diffuse midline glioma, H3 K27M-mutant	sensitive	Alpelisib	Preclinical - Cell culture	Actionable	In a preclinical study, Piqray (alpelisib) inhibited viability of mouse glioma cells expressing H3.3 K28M (reported as H3.3 K27M) and FGFR1 N546K (reported as N457K) in culture (PMID: 37011011).	37011011