Research > Focus A > Work Packages A05
Summary
By analysis of the mutational spectrum, DNA methylation patterns, chromosomal aberrations, and proteome profiles of tumor tissues from glioblastoma patients with O6-methylguanine DNA-methyltransferase (MGMT) promoter methylation and response (>15 months progression-free-survival) vs. patients with no response (<6 months) to combined radiochemotherapy with temozolomide, we aim to identify novel predictive tissue-biomarkers for temozolomide response and resistance in glioblastoma patients. These novel predictive markers are expected to have a direct impact on clinical decision making with improved predictive power when compared to MGMT methylation status alone. The visual abstract below shows the aims and planned tasks of the work package.
Based on the findings of work package A05 there was a shift in reserach focus for the second funding period. The follow-up project aims at in depth characterization of the unusual EGFR-fusions identified in long term survivors using state-of-the-art mass-spectrometry based proeteomics and interactomics (C06).
Task 1
Discovery:
Proteogenomic profiling of a retrospective cohort of glioblastomas mMGMT with (n=25) and without (n=25) response to treatment
Steps / Workflow
- Genome wide DNA methylation
- MicroRNA expression
- Whole genome sequencing
- Whole transcriptome sequencing
- Whole proteome profiling
- Whole phospho-proteome profiling
Task 2
Candidate identification:
Integration of data for identification of genes, proteins and pathways relevant to TMZ response or resistance. Selection of candidates for targeted profiling and functional characterization
Steps / Workflow
- Identification of most significantly associated genes, proteins and pathways
- Candidate selection for targeted profiling and functional characterization
Task 3
Candidate analysis:
Analysis of candidates in a series of 100 glioblastomas mMGMT (no selection for treatment response)
Steps / Workflow
- Genome wide DNA methylation
- Panel sequencing of DNA / RNA
- Targeted proteomics with Parallel Reaction Monitoring
- Data analysis and correlation with clinical data (PFS)
Task 3
Validation:
Analysis of candidates in two independent series of glioblastomas mMGMT (n=100) and uMGMT (n=100).
Steps / Workflow
- Validation of candidates
- Re-translation to immunohistochemistry level
- Implementation in diagnostic procedure
PRINCIPLE INVESTIGATORS
VON DEIMLING, ANDREAS, PROF. DR. MED.
Chair / Head of Department
University Hospital Heidelberg, Institute of Pathology, Department of Neuropathology & DKFZ, Clinical Cooperation Unit Neuropathology, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany
REUSS, DAVID E., PD DR. MED.
Chief Consultant
University Hospital Heidelberg, Department of Neuropathology, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany