An integrated analysis of data derived from 99 treatment-naive glioblastomas has identified characteristics that could help stratify patients for more effective treatment, according to the investigators.
The analysis provides a detailed map of genes, proteins, infiltrating cells, and signaling pathways that play key roles in driving glioblastoma,, of Washington University in St. Louis, and colleagues reported in .
For example, the team identified key phosphorylation events as potential mediators of oncogenic pathway activation and potential targets for EGFR-, TP53-, and RB1-altered tumors. Specifically, phosphorylated PTPN11 and PLCG1 represent a signaling hub in RTK-altered tumors, they found.
The investigators also identified four immune glioblastoma tumor subtypes characterized by distinct immune cell populations. Type 1 tumors have a high macrophage count and few T cells, type 2 tumors have a moderate macrophage count, type 3 tumors have a high T-cell count and few macrophages, and type 4 tumors have few or no immune cells of any type.
They also found that mesenchymal subtype EMT signature is specific to tumor cells but not to stroma, and histone H2B acetylation is enriched in classical glioblastomas with low macrophage content.
“To improve therapies for this deadly cancer, understanding the tumor cells themselves is important but not enough,” senior author Li Ding, PhD, a professor of medicine and genetics and director of computational biology in the division of oncology at Washington University stated in a. “We also must understand the tumor cells’ interactions with the surrounding environment, including immune cells and the connective tissues and blood vessels.”
The investigators, including researchers from Pacific Northwest National Laboratory, Case Western Reserve University, and the National Cancer Institute, performed high-resolution and high-depth analyses on 99 tumors.
“Harnessing new technologies, including proteomics, metabolomics, and single-cell sequencing, this study is an extremely deep dive into glioblastoma tumor biology, revealing new possibilities for therapy,” Dr. Ding said.
The study, which is part of the NCI’s, is the largest and most detailed schematic of glioblastoma tumors to date, according to the press release.
The most immediate implication of the findings is better clinical trial design, study coauthor, stated in the press release.
Stratifying patients by tumor type, as identified in the current analysis, could allow researchers to test targeted therapies in the tumors most likely to respond to those therapies, explained Dr. Chheda, of Siteman Cancer Center at Barnes Jewish Hospital and Washington University.
The findings, particularly of multiple glioblastoma tumor subtypes, may explain the negative findings of trials looking at various immunotherapies for treating glioblastoma. Investigators for those trials haven’t considered the possibility of immune subgroups that may respond differently, the authors note, adding that research is underway to identify the best drugs to assess for the newly identified glioblastoma tumor types.
The study was supported by grants from the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium, the National Human Genome Research Institute, and the National Institutes of Health.
Dr. Wang and Dr. Ding reported having no disclosures. Dr. Chheda receives research support from NeoimmuneTech and Orbus Therapeutics, and royalties from UpToDate.