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Integrated Proteogenomics Uncover Mechanisms of Glioblastoma Evolution, Pointing to Novel Therapeutic Targets
Jiabo Li1, Ling-Kai Shih1, Daniel J Brat1
1Department of Pathology, Northwestern Medicine Malnati Brain Tumor Institute of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
Abstract:
Nearly all glioblastoma (GBM) patients relapse following standard treatment and eventually succumb to disease. While large-scale, integrated multiomic studies have tremendously advanced the understanding of primary GBM at the cellular and molecular level, the posttherapeutic trajectory and biological properties of recurrent GBM remain poorly understood. This knowledge gap was addressed in a recent Cancer Cell article in which Kim and colleagues report on a highly integrative proteogenomic analysis performed on 123 matched primary and recurrent GBMs that uncovered a dramatic evolutionary shift from a proliferative state at initial diagnosis to the activation of neuronal and synaptogenic pathways at recurrence following therapy. Neuronal transition was characterized by posttranslational activation of WNT/PCP signaling and BRAF kinase, while many canonical oncogenic pathways, and EGFR in particular, were downregulated. Parallel multiomics analyses of patient-derived xenograft (PDX) models corroborated this evolutionary trajectory, allowing in vivo experiments for translational significance. Notably, targeting BRAF kinase disrupted both the neuronal transition and migration capabilities of recurrent gliomas, which were key characteristics of posttreatment progression. Furthermore, combining BRAF inhibitor vemurafenib with temozolomide prolonged survival in PDX models. Overall, the results reveal novel biological mechanisms of GBM evolution and therapy resistance, and suggest promising therapeutic intervention.
Insights
Glioblastoma (GBM) evolves after treatment, shifting from proliferation to neuronal pathways. Targeting BRAF kinase offers a promising therapeutic strategy for recurrent GBM, improving survival in models.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Glioblastoma (GBM) frequently relapses after standard therapy, with limited understanding of its post-treatment evolution.
- Previous multiomic studies advanced primary GBM knowledge but left recurrent GBM biology under-explored.
Purpose of the Study:
- To investigate the molecular and cellular changes driving glioblastoma recurrence after therapy.
- To identify therapeutic targets for recurrent glioblastoma by analyzing its evolutionary trajectory.
Main Methods:
- Proteogenomic analysis of 123 matched primary and recurrent glioblastoma samples.
- Multiomic analysis of patient-derived xenograft (PDX) models to validate findings and enable in vivo experiments.
Main Results:
- Recurrent glioblastoma exhibits a significant evolutionary shift from a proliferative state to activated neuronal and synaptogenic pathways.
- Neuronal transition involves posttranslational activation of WNT/PCP signaling and BRAF kinase, with concurrent downregulation of pathways like EGFR.
- Targeting BRAF kinase inhibited neuronal transition and migration in recurrent gliomas, and combination therapy (BRAF inhibitor + temozolomide) prolonged survival in PDX models.
Conclusions:
- Glioblastoma undergoes a dramatic evolutionary shift post-therapy, characterized by neuronal pathway activation and therapy resistance.
- BRAF kinase is a key driver of this neuronal transition and migration, representing a potential therapeutic target.
- Combined BRAF inhibition and standard chemotherapy show promise for treating recurrent glioblastoma.
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