TARGETING TUMOR PROPAGATING CELLS IN GLIOBLASTOMA: FROM MECHANISTICINSIGHTS TO PRECISION MEDICINE

Background and Rationale. There is a crucial need to identify novel therapeutic strategies against glioblastoma(GBM), in particular for the eradication of subpopulations of tumor propagating cells - referred to as glioblastoma stem-like cells (GSCs) - that display phenotypic plasticity and drive DNA repair and resistance to current radio- and chemotherapy. We have identified a CXCL12-CXCR4-AurA axis that drives invasion of GSCs into the subventricular zone (SVZ), and shown that this niche fosters DNA repair and resistance to ionizing radiation (IR). In addition, we have described a unique gene expression signature that results in a novel classification of GBM specimens in two major groups (G1 and G3) displaying profound differences in proliferation as well as DNA repair and cell-cycle gene expression, and exposing distinct vulnerabilities. Aims and Experimental Strategy. We plan to investigate the interplay between the SVZ and GSCs of the G1 and G3 groups and examine whether there are intrinsic differences in the ability of G1 and G3 GSCs to invade the SVZ and mount a DNA damage response (DDR) leading to IR resistance. In this context, specific objectives include:1) To characterize the genomic landscape and molecular features of the G1 and G3 tumors 2) To investigate the replication stress and DDR mechanisms underlying G1 and G3 GSCs3) To characterize the interplay between the SVZ and GSCs of the G1 and G3 groups 4) To target DNA repair pathways in G1 and G3 GSCs Expected Results and Potential Impacts. We strongly believe that our experiments will unravel the phenotypic differences between G1 and G3 GSCs as well as their underlying molecular basis and associated vulnerabilities, thus shedding new light in cancer stem cell biology while contributing to mechanism-based classification and precision medicine for GBM.