SYS-GLIO

Systems‐based predictors for the biological and clinical behavior of gliomas

Diffusely infiltrating astrocytic gliomas are the most common intrinsic brain tumors and cover a spectrum of malignancy grades, ranging from diffuse astrocytoma (WHO grade II) over anaplastic astrocytoma (WHO grade III) to glioblastoma (WHO grade IV). Clinically, two types of glioblastomas are distinguished, i.e. primary glioblastomas that arise de novo with a short clinical history, and secondary glioblastomas that develop by progression from a preexisting lower grade glioma. Despite sharing similar histological features, primary and recurrent glioblastomas carry distinct genomic, epigenetic and transcriptional aberrations for review see. Glioblastomas carry a universally dismal prognosis in children and adults with median survival times still below 12 months from diagnosis. In this project we want to analyze the genetic characteristics of malignant brain tumors of different WHO grade greater detail. With the results of these investigations we want to develop new strategies to stop the malignant progression of low-grade gliomas and prevent drug resistance in high grade lesions.

Graphical representation of the interdisciplinary systems medicine approach that will be pursued in SYS-GLIO. The project is based on high-throughput molecular data generated through independent intramural funding by profiling different types of gliomas at multiple levels, including longitudinal results obtained by molecular studies of primary and recurrent tumor pairs of individual patients. These data sets are being used for integrative bioinformatics and modeling in WP1. The resulting predictions are being tested using both clinical samples from glioma patients (WP2) and preclinical model systems (WP3). Experimental results are than fed back to WP1 for optimization of the in silico models, which in turn will lead to successful clinical translation, including the establishment of novel molecular biomarkers for patient stratification and the characterization of new molecular targets for individualized therapeutic approaches. These will be the basis for the development of clinical trial protocols (WP4).

Subprojects in SYS-GLIO:

SP 1A Integrative analysis of genome-wide data sets

SP 1B Mathematical modeling of glioma growth

SP 2A Assessment of crucial pathways in validation cohort

SP 2B Assessment of crucial pathways in validation cohort

SP 3A In vivo validation in glioma mouse models

SP 3B Experimental modeling of glioma progression and therapy resistance

SP 3C Metabolic adaptations in glioma progression and therapy resistance

SP 4 Development of a clinical trial protocol