Cancer stem cells (CSCs) are a critical tumor subpopulation that may cause local recurrences that plague patients with advanced solid malignancies, even after maximal therapeutic efforts. CSCs can self-renew, differentiate into multiple lineages, resist radiation and chemotherapy, and efficiently initiate and propagate tumor formation. These characteristics make the quest for assays to measure drug efficacy on CSCs an urgent focus of drug discovery. We propose to identify potential brain tumor stem cell (BTSC) biomarkers- unique small molecule metabolites secreted only by BTSCs- that indicate therapeutic efficacy in CSCs. We will first determine a preliminary BTSC metabolomic footprint by profiling three BTSC cell lines using high-throughput, sensitive mass spectrometry to detect secreted metabolites. Then we will compare the BTSC metabolomic footprint with the footprints of glioblastoma multiforme tumor cells and neural stem cells to establish BTSC-specific metabolites, the biomarkers. Using targeted metabolite profiling for these biomarkers, we will assess the efficacy of varioous therapeutic agents against BTSCs in vitro after treatment with standard anti-GBM agents and novel theraputics, and correlate efficacy with differential levels of the monitored BTSC-specific metabolites. If successful, we will later conduct in vivo studies based on the efficacy correlations from these in vitro studies.
