Integrated proteogenomic characterization of glioblastoma evolution

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Glioblastoma (GBM) evolution is complex, involving more than genetic changes.
• Understanding GBM recurrence and treatment resistance is critical for improving patient outcomes.

Purpose of the Study:

• To investigate the evolutionary mechanisms of glioblastoma (GBM) using an integrative proteogenomic approach.
• To identify molecular pathways driving GBM recurrence and therapeutic resistance.

Main Methods:

• Integrative proteogenomic analysis of 123 longitudinal glioblastoma pairs.
• Proteomic and phosphoproteomic profiling of tumor samples.
• Multi-omic analysis of patient-derived xenograft (PDX) models.

Main Results:

• Identified a shift from a proliferative state at diagnosis to neuronal and synaptogenic pathways in recurrent GBM.
• Discovered post-translational activation of WNT/PCP signaling and BRAF kinase in recurrent tumors.
• Demonstrated that BRAF inhibition impairs neuronal transition and migration, and combinatorial treatment with temozolomide (TMZ) extends survival in PDX models.

Conclusions:

• Glioblastoma evolution involves a switch to a neuronal-like state characterized by WNT/PCP and BRAF pathway activation.
• Targeting BRAF kinase presents a promising therapeutic strategy, particularly in combination with temozolomide (TMZ), to overcome glioblastoma recurrence and treatment resistance.