Experimental modeling of glioma progression and therapy resistance
The subproject 3B focuses on the experimental modeling of molecular mechanisms of drug resistance of glioma and the functional analysis of the role of genetic and epigenetic alterations of response to therapy and the malignant progression of gliomas in vitro and in vivo. TP 3B thus forms an experimentally oriented counterpart to the molecular high-throughput analysis of human tissue samples before and after treatment and before and after tumor progression, as well as the acts building upon systems biology modeling (TP 1 and TP 2A). Various existing cell culture models are used in TP 3B to characterize genome, methylome and transcriptome-wide high-throughput analysis, the underlying molecular mechanisms of development of resistance of temozolomide (TMZ) treatment in gliomas. Furthermore, on the basis of these models functional analyses are conducted to influence the TMZ-sensitivity through targeted overexpression or knockdown of candidate genes for which there is evidence from other subprojects of SYS-GLIO for a role in the resistance to therapy. A second focus of the project is the experimental modeling of the development and malignant progression of IDH1 mutant gliomas. Existing neural stem and progenitor cell cultures serve as a model in which functional effects of the targeted modulation of progression-associated candidate genes both in vitro and in vivo are to be evaluated in orthotopic transplantation experiments.