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Pediatric Brain Tumor Proteomics Highlight Possible Treatment Targets, Biomarkers

NEW YORK – Members of the Children's Brain Tumor Tissue Consortium and the Clinical Proteomic Tumor Analysis Consortium used proteogenomics to search for biological, biomarker, and therapeutic clues across several pediatric brain cancer types, uncovering tumors with possible treatment targets that clustered together proteomically across distinct histological tumor types.

"The current study is the first to reveal in pediatric brain tumors the power of proteins to better determine which patient might benefit from a given therapy, and our validation studies using targeted proteomics provide a platform for clinical implementation of the findings," co-senior author Amanda Paulovich, a researcher affiliated with the Fred Hutchinson Cancer Research Center, said in a statement. 

For their retrospective analyses, published in Cell on Wednesday, the researchers brought together genomic, transcriptomic, quantitative proteomic, and phosphoproteomic insights from more than 200 pediatric tumors spanning seven brain cancer types or histological subtypes that were collected through the Children's Hospital of Philadelphia's Children's Brain Tumor Tissue Consortium.

"Pediatric cancers in general, and pediatric brain tumors in particular, have a relatively low mutational burden," co-senior and co-corresponding author Pei Wang, a genetics and genomic sciences researcher at Icahn School of Medicine at Mount Sinai, said in a statement, adding that "comprehensive characterization of the functional molecular biology of these tumors, including the proteogenomic analysis done in this study, is essential to better understand and treat pediatric brain tumors."

The team's dataset encompassed whole-genome sequence, RNA sequence, mass spectrometry-based proteomic, and phosphopeptide enrichment-, liquid chromatography-, and tandem mass spec-based phosphoproteomic data on up to 218 pediatric brain tumors, including 93 low-grade gliomas, more than two dozen high-grade glioma tumors, 22 medulloblastoma cases, 32 ependymomas, 18 ganglioglioma tumors, 16 tumors representing craniopharyngioma, and 12 atypical teratoid rhabdoid tumors.

Based on their analyses, the researchers highlighted a pediatric craniopharyngioma subgroup with proteomic and phosphoproteomic features resembling those in BRAF V600E-mutated low-grade gliomas, for example, suggesting that they may benefit from MEK inhibitors used in that tumor type.

"This observation suggests potential use of MEK/MAPK inhibitors in a subset of pediatric [craniopharyngioma], which currently has no robust chemotherapy options," they reported, noting that apparent proteomic/phosphoproteomic craniopharyngioma subgroups were not picked up with available transcriptome data.

Likewise, the team tracked down protein biomarkers — IDH1 and IDH2 — that appeared to coincide with clinical outcomes such as tumor aggressiveness and survival in children with high-grade glioma tumors that lack a prognostic genetic mutation in a histone H3.3-coding gene. That finding was bolstered by additional tandem mass tag testing on tumor samples from dozens more pediatric high-grade glioma cases.

"This project represents a significant advance in biological interrogation of pediatric brain tumors at multiple levels of biological control and across traditional histological boundaries," the authors wrote, though they cautioned that "the limited sample sizes of some histologies pose a significant limitation for certain investigations."