A comprehensive “proteogenomic” analysis has been completed of the proteins, genes, and RNA transcription in pediatric brain tumors, which are the leading cause of cancer-related deaths in children. The project was carried out by researchers from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and Children’s Brain Tumor Network (CBTN). It is the first of its kind, and is aimed at improving diagnosis and treatment. The study was available online in Cell today, November 25.
In this initial published report from the study, the researchers have already made important findings about how treatments for one type of pediatric brain tumor may be useful in another. These include new insights into treatments for a subtype of craniopharyngioma that currently has no robust treatment option and for high-grade gliomas. In addition, the data showed key biological differences in samples from primary and recurrent tumors from the same patients, indicating that these tumors need independent assessment and possibly different treatments.
“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” said co-author Amanda Paulovich, MD, PhD, Aven Foundation Endowed Chair and professor in the Clinical Research Division at Fred Hutchinson Cancer Research Center.
The consortium comprises collaborators from the Icahn School of Medicine at Mount Sinai, National Cancer Institute, Fred Hutchinson Cancer Research Center, Children’s National Hospital, and Children’s Hospital of Philadelphia.
This study analyzed genomics, transcriptomics, global proteomics, and phosphoproteomics across a cohort of 218 tumor samples representing seven distinct types of brain tumors: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12).
They write that they took this comprehensive approach because: proteomic clusters reveal actionable biological features spanning histological boundaries, proteomics reveals downstream effects of DNA alterations not evident in transcriptomic, and kinase activity analyses provide insights into pathway activities and druggable targets
One of their key findings is based on results from two distinct subgroups of pediatric craniopharyngioma. One subgroup showed proteomic/phosphoproteomic characteristics that were strikingly similar to those of another type of tumor, known as low-grade glioma (LGG) with BRAFV600E mutation. This observation suggests that MEK/MAPK inhibitors, a type of chemotherapy that has been used against LGG-with-BRAFV600E-mutation tumors, might also help with this subset of craniopharyngiomas, which currently has no robust chemotherapeutic options.
The research team also identified new prognostic biomarkers for a type of tumor known as high-grade glioma (HGG). When HGG tumors have a genetic mutation known as a H3K27M mutation, they tend to be very aggressive and the patients have relatively short survival time. However, in those without the mutation, this study suggests that the abundance of proteins named IDH1 and IDH2 in the tumor tissues could help to identify which tumors with the non-mutated H3K27M gene may be less aggressive.
“The driver of this joint study has been a commitment to data-sharing and open science. Coming together has given both CPTAC and CBTN an opportunity to expand our available resources for answering critically important biological questions. Harnessing the collective expertise across these consortia enables us to better understand the mechanisms of pediatric tumors, improve the process of target protein identification, and potentially improve cancer treatments,” said Adam Resnick, Ph.D., contributing researcher, Scientific Co-Chair for CBTN, and Director of the Center for Data Driven Discovery in Biomedicine (D3b) at Children’s Hospital of Philadelphia.
“Integration of the clinical, proteomic, and genetic data generated in this study allows us to construct a more comprehensive model of brain tumor biology, which will lead to more targeted treatments,” added Brian Rood, M.D., contributing researcher, Executive Co-Chair for CBTN, and Medical Director of the Brain Tumor Institute at Children’s National Hospital.