Pediatric glioma proteogenomics identifies age-linked targets, not therapies

A proteogenomic study of high-grade glioma in patients from infancy through age 40 identified tumor-related molecular changes that varied with age and sex, highlighting a molecular transition around age 26 and nominating four kinases as candidate treatment targets. The observational research analyzed 112 patient tumors, while experimental work in tumor-derived cell lines showed that blocking selected kinases slowed growth when the corresponding kinase was highly active. These results identify candidates for further investigation rather than establish effective treatments in patients; the authors said important findings require confirmation in larger studies, and targets such as CDK8 need validation in animal models before clinical testing.

Researchers from the Icahn School of Medicine at Mount Sinai and collaborating institutions examined high-grade glioma, an aggressive primary brain tumor reported to have a five-year survival rate below 10%. Pediatric and adolescent and young adult patients were a particular focus because tumors in children differ markedly from those in adults, while disease in patients aged roughly 15 to 40 is often understudied and does not fit neatly into either pediatric or adult classifications. The study was conducted through the Clinical Proteomic Tumor Analysis Consortium of the National Cancer Institute, the Children’s Brain Tumor Network and the Philadelphia Coalition for a Cure.

The main dataset contained tumor samples from 112 patients aged 83 days to 40 years. Investigators measured DNA, RNA, proteins and chemical modifications made to proteins after they are produced, including phosphorylation and glycosylation. These layers were combined with data from 99 adult glioblastoma tumors and with clinical and genetic information from a reference group of more than 5,000 people with high-grade glioma. The researchers used this broader information to follow molecular patterns across the lifespan and to distinguish cancer-associated features from changes related to normal brain development, which varies with both age and sex.

By tracing molecular profiles continuously across age rather than sorting patients only into established tumor subtypes, the team identified a distinct shift around age 26 within the range often grouped clinically as adolescents and young adults. Patients aged 15 to 26 and those aged 26 to 40 had different molecular profiles, survival outcomes and signaling programs. Comparisons with normal brain tissue across the same age span showed that age- and sex-related changes in oxidative phosphorylation occurred in tumors but were not observed in normal brains. This supported the interpretation that the metabolic differences were associated with tumor processes rather than normal development, although the observational analysis did not establish the cause of the transition.

Oxidative phosphorylation was also central to the target analysis. Computational analysis and laboratory validation identified CDK8, ATM, ATR and LCK, four kinases involved in controlling cell signaling, as potential treatment targets. In tumor-derived cell lines, gene editing or drug treatment slowed growth when the corresponding kinase was most active. CDK8 was a particularly notable candidate because it is less well characterized in high-grade glioma than the established targets ATM and ATR. The analysis indicated that CDK8 suppresses oxidative phosphorylation, which the study associated with more favorable survival; this molecular relationship does not demonstrate that CDK8 inhibition will improve survival in patients.

The analysis also revealed substantial differences between male and female patients. About 27% of the measured proteins had different age-related trajectories in the two groups. A prognostic score established in earlier work was associated with outcomes among male patients but not female patients. Glycosylation, the attachment of sugar structures to proteins, supplied more survival-associated features in males than in females, providing information that the other molecular layers did not capture as fully. Protein-based grouping also identified a previously unrecognized male subgroup with the poorest survival observed in the study, distinguished by immune-signaling features and characteristics of the tissue surrounding the tumor.

Immune features also showed different associations in male and female patients. Higher levels of infiltrating T cells were associated with better outcomes in females but not in males. A pattern involving PDCD1, the gene that codes for the PD-1 immune checkpoint protein, was seen only in male pediatric and young-adult patients. Because PD-1 inhibitors are already being studied in this population, the authors said these findings support further investigation of treatment strategies that account for sex differences. The reported patterns describe associations in tumor samples; the supplied findings do not establish that a checkpoint inhibitor has greater clinical efficacy in either sex or that treatment response differs between male and female patients.

Lead first author Nicole Tignor said the multi-layer analysis allowed the investigators to examine the same genes across DNA, RNA, proteins and protein modifications. She said glycosylation captured aspects of tumor biology missed by other molecular data and might be especially valuable for understanding sex differences in immune responses and, potentially, treatment response. That potential remained a rationale for additional study rather than a demonstrated clinical effect. Lead contact author Pei Wang said analyzing tumors in their developmental context can help researchers make better use of patient data and identify patterns that might otherwise be missed.

Several limitations constrain the findings. High-grade glioma is rare in children, and sample sizes become smaller when patient data are divided by age, sex and tumor features. To address this challenge, the team developed an analytic method that applies molecular trajectories learned in one group to help interpret survival patterns in another. Even with that approach, some age- and sex-specific findings may reflect sampling variation and will need confirmation in larger cohorts. Candidate targets such as CDK8 require validation in animal models before clinical testing, and the mechanisms underlying the observed differences between male and female patients remain to be defined.

Together, the findings indicate that high-grade glioma arising during brain development cannot be characterized adequately by a simple pediatric-versus-adult distinction or by one molecular layer alone. Age, sex and developmental context shaped measurable features of the tumors and may therefore matter when interpreting prognosis, designing clinical trials and prioritizing therapeutic studies. The Children’s Brain Tumor Network and the consortium are continuing to collect samples and generate data across pediatric brain tumors and other childhood cancers. The researchers said those larger datasets will be needed to determine which patterns occur across cancers, which are specific to high-grade glioma and which are most promising for therapeutic development.

Subject of Research: Proteogenomic analysis of age- and sex-associated biology and candidate kinase targets in pediatric and young-adult high-grade glioma

Article Title: Study identifies candidate treatment targets for high-grade glioma in children and young adults

Article References: Study identifies candidate treatment targets for high-grade glioma in children and young adults. Original publication (Bibliographic details unavailable.)

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Keywords: high-grade glioma, pediatric brain cancer, young-adult cancer, proteogenomics, kinase targets, CDK8, oxidative phosphorylation, sex differences, glycosylation, cancer metabolism, identifies, candidate