Oncology is the poster child for the development of personalized systems medicine approaches based on the translation of omics-type profiling data into patient care. Brain tumors are particularly suited for novel integrated systems medicine approaches for personalized therapy because current treatment options are limited and the prognosis of the vast majority of these neoplasms remains grim. Because most gliomas are driven by genomic alterations that are currently not druggable, genomic characterization alone has had limited clinical success so far. Adding a tumor (phospho)proteome component to morpho-genomic data to identify new targetable molecular lesions and to select biomarkers that can be directly translated into experimental clinical use is thus a consequent next step forward. The currently established molecular tumorboards at large cancer centers of excellence as well as the overarching pan-German MASTER (Molecularly Aided Stratification for Tumor Eradication) clinical registry trial stratify cancer patients without satisfactory therapeutic options for experimental therapies based on genome, transcriptome and methylation profiling data and follows patients to assess the usefulness of broad individualized molecular characterization in patient care. Data from the therapeutically important layer of the (phospho)proteome is currently not included, the current stratification approaches are mere descriptive and do not rely on functional characterizations.
To close this gap, an intradisciplinary team of scientists working on CLINSPECT-M’s workpackage 4 performs comprehensive quantitative (phospho)proteome profiling on a retrospective cohort of glioma patients (selected from molecular tumor boards) as well as on prospective molecular tumor board cases. This approach will greatly expand our knowledge regarding feasibility of (phospho)proteomic profiling by mass spectrometry in the context of large-scale personalized patient stratification programs and the potential of (phospho)proteome data to improve recommendation of experimental therapies in molecular tumor boards.
A team of highly-qualified neurosurgeons around Prof. Bernhard Meyer (Department of Neurosurgery, University Hospital Rechts der Isar) works on the selection of appropriate glioma patients. They implement a CLINSPECT-M database and use the omics data generated in WP4 to assess differences in clinical molecular tumor board recommendations comparing the standard genomics approach with the proteogenomic approach. Morphological assessment and annotation is performed by experienced pathologists from the team of Prof. Wilko Weichert (Institute of General and Surgical Pathology, Technical University of Munich), who co-coordinates the pan-German MASTER registry trial and is one of the coordinators of the molecular tumor board of the Comprehensive Cancer Center Munich (CCCM), including more than 1000 patients per year. The team developed and executes specific (phospho)protein extraction protocols on the formalin-fixed paraffin embedded routine diagnostic tumor material from included glioma patients.
The extracted analytes are submitted to a standardized, robotic workflow optimized for high-throughput, quantitative (phospho)proteomics. This part of the work is performed by a team of proteomic experts from the lab of Prof. Bernhard Küster (Chair of Proteomics and Bioanalytics, Technical University of Munich). The analysis of all proteomic and phosphoproteomic profiles using state-of-the-art bioinformatic approaches and the development of new software tools to generate automated reports of proteogenomic data for the molecular tumor board is taken care of by a team of highly-qualified bioinformaticians around Prof. Julien Gagneur (Computational Molecular Medicine, Technical University of Munich). This interdisciplinary team of outstanding scientists works closely together towards the common goal of providing and integrating multiple Omics level data to molecular tumor boards to improve recommendations for targeted molecular therapies and novel immunotherapeutic approaches.