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|Ref Type||Journal Article|
|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.|
|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.|
|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|
|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|
|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|