Researchers at the Icahn School of Medicine at Mount Sinai and collaborators have identified candidate treatment targets and potential prognostic markers for high-grade glioma (HGG), an aggressive brain cancer in children, adolescents, and young adults (AYA). The study found that high-grade glioma varies by developmental stage and sex, showing distinct tumor biology and outcomes across patient groups.
The team carried out proteogenomic analyses of tumors from more than 100 HGG patients aged 0–40 years. Their multiomics analysis identified two AYA age groups with distinct molecular profiles and survival outcomes.
The researchers suggest that using the study results to guide clinical trial design and develop new therapies could advance more precise treatment strategies.
“Our goal was to understand high-grade glioma from infancy through young adulthood and identify tumor-related changes tied to outcomes such as survival,” said Pei Wang, PhD, professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai. “Because age and sex shape normal brain development, we wanted to separate features of the cancer from those associated with a patient’s developmental stage.”
The study was conducted by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) of the National Cancer Institute (NCI), the Children’s Brain Tumor Network, and the Philadelphia Coalition for a Cure.
Wang, and Avi Ma’ayan, PhD, Mount Sinai endowed professor in bioinformatics and director of the Mount Sinai Center for Bioinformatics, are principal investigators of the Proteogenomic Data Analysis Center at the Icahn School of Medicine, part of CPTAC.
Wang is co-senior and co-corresponding author of the researchers’ published paper in Cell Reports Medicine, titled “Proteogenomic analysis of pediatric and AYA high-grade glioma reveals age-dependent biology, female-male differences, and candidate kinase targets.” In their paper the investigators concluded, “This study provides an integrated multiomics analysis of HGGs across development, establishing a framework in which age and developmental context shape tumor biology.”
High-grade glioma is among the most aggressive primary brain tumors, with a five-year survival rate below 10%. Tumors in children differ markedly from those in adults, while adolescents and young adults remain especially understudied because their tumors do not fit neatly into either pediatric or adult disease. “High-grade gliomas (HGGs) in children and adolescents and young adults (AYA) exhibit distinct biology across the neurodevelopmental spectrum,” the authors wrote. “Differences between male and female patients, which influence both brain development and cancer biology, represent another underexplored dimension.”
Because age and sex shape normal brain development, the researchers sought to distinguish tumor-related molecular features from those associated with developmental stages. Working with CPTAC, the team profiled tumors—samples were collected through the Children’s Brain Tumor Network—from 112 patients aged 83 days to 40 years, measuring DNA, RNA, proteins, and chemical changes made to proteins after they are produced, including phosphorylation and glycosylation.
Those measurements were combined with data from 99 adult glioblastoma tumors and clinical and genetic information from a reference group of more than 5,000 people with high-grade glioma, to trace how tumor biology changes across the lifespan.
Using computational analysis and laboratory validation the team identified as potential treatment targets several kinases—enzymes that help control cell signaling—including CDK8, ATM, ATR, and LCK.
Studies showed that in tumor-derived cell lines, blocking these kinases through gene editing or drug treatment slowed growth when the corresponding kinase was most active. CDK8 emerged as a particularly notable candidate because it is less well characterized in high-grade glioma than established targets such as ATM and ATR. Analyses indicated that CDK8 suppresses oxidative phosphorylation (OXPHOS), a key energy-producing process that the study linked to more favorable survival. “Causal network analysis and cell line studies provide a rationale for personalized therapies targeting candidate kinases, such as CDK8,” the investigators noted.
By tracing molecular profiles continuously across age rather than sorting patients into established tumor subtypes the researchers identified a clear shift around age 26 years within an age range often grouped clinically as adolescents and young adults. The two study groups (adolescents aged 15 years to 26 years and young adults aged 26 years to 40 years) had distinct molecular profiles and survival outcomes and relied on different signaling programs.
Comparing tumors with normal brain tissue across the same age span sharpened the picture. Oxidative phosphorylation showed age- and sex-related changes in tumors that were not seen in normal brains, suggesting these differences arise from tumor processes rather than normal development.
About 27% of the proteins the team measured showed different age-related trajectories in male and female patients. A prognostic score established in earlier work was associated with outcomes in male patients but not in female patients. Glycosylation proved especially informative in male patients, with far more survival-associated features than in female patients. Protein-based grouping also revealed a previously unrecognized male subgroup with the poorest survival in the study, distinguished by immune signaling and features of the tissue surrounding the tumor.
“CPTAC allows us to examine the same genes across several layers of biology, from DNA and RNA to proteins and protein modifications,” said first author Nicole Tignor, PhD, assistant professor of genetics and genomic sciences at the Icahn School of Medicine “In this study, glycosylation captured aspects of tumor biology missed in other molecular data. It may be especially valuable for understanding differences between male and female patients in immune responses and, potentially, treatment response.”
Higher levels of infiltrating T cells were associated with better outcomes in female patients but not in male patients, while a pattern involving the immune checkpoint gene PDCD1, which codes the protein PD-1, was seen only in male pediatric and young adult patients. Because PD-1 inhibitors are already being studied in this population, the authors say the findings support further study of treatment strategies that account for these differences. “Our integrated analysis also revealed immune cell types associated with survival,” they noted. “T cell infiltration was linked with favorable outcomes in female PED/AYA HGG patients but not in male counterparts and correlated with PD-1 expression only in males, a pattern absent in adult tumors (>40 years),” the investigators stated.
They pointed out that that sex-related differences have emerged as an important determinant of immune response in glioblastoma, with evidence indicating that that male patients may exhibit greater sensitivity to the immune checkpoint blockade. “As PD-1 inhibition therapies are under active investigation in clinical trials involving PED/AYA HGG patients, our findings support the development of male and female-specific treatment strategies.”
The authors further noted that sample sizes are limited, which is a persistent challenge in rare pediatric cancers that is more pronounced when patient data are divided by age, sex, and tumor features. The team developed an analytic approach that uses molecular trajectories learned in one group to help interpret survival patterns in another. Even so, the team noted, some findings will need confirmation in larger studies, and targets such as CDK8 will require validation in animal models before clinical testing.
The mechanisms underlying the observed differences between male and female patients also remain to be defined. Nevertheless, the investigators concluded, despite limitations, “… our study advances understanding of the developmental patterns in male and female HGGs and identifies molecular and immunologic features with translational potential.”
Wang added, “Patient data are becoming increasingly rich, but they also reflect cancers arising at different ages and in different biological settings. How we account for that variation affects which biological signals we can detect. Analyzing tumors in their developmental context can help us make better use of these data and identify patterns that might otherwise be missed.”
The Children’s Brain Tumor Network and CPTAC are continuing to collect samples and generate data across pediatric brain tumors and other childhood cancers. The team will use those larger datasets to determine which patterns hold across cancers, which are specific to high-grade glioma, and which are most promising for therapeutic development.
The study’s proteogenomic datasets are publicly available through the NCI Proteomic Data Commons and the Children’s Brain Tumor Network, and the analysis code has been released openly.
