ABSTRACT The median survival time of glioblastoma multiform (GBM) patients is only 15 months from initial diagnosis, making it the most aggressive and lethal form of adult brain tumor. The World Health Organization (WHO) classifies GBM as a grade IV tumor (the highest grade), and only 5% of the GBM patients survive 5 years or longer after diagnosis. The poor prognosis and high mortality rates of GBM are due, in part, to the stem-like tumor-propagating cells present in the GBM. Although these GBM stem-like cancer populations are believed to contribute to therapeutic resistance and cancer recurrence, the underlying mechanism of stem cell induction and maintenance, is not fully understood. The ultimate goals of this proposal are to identify stem- specific genes controlled by two key transcription factors and develop novel DNA methylation technologies to eliminate GBM stem populations. The transcription factors SALL2, SOX2, OLIG2 and POU3F2 are required for reprogramming differentiated GBM cells into stem-like tumor propagating cells. Of these proteins, only SALL2 appears to physically interact with SOX2. This will be the first investigation to evaluate the pathological consequences of the interaction between SALL2 and SOX2, identifying its target genes and determining their roles in driving GBM stem populations (Specific Aim I). In addition, this will be the first experimental approach to precisely target the SALL2 promoter for methylation, blocking its expression and thus eliminating GBM stem-like cancer cells (Specific Aim II). Completion of these aims will substantially increase our understanding of how GBM stem-like cells are induced and maintained. Our innovative approaches will facilitate the development of novel methylation-mediated therapeutics to block therapeutic resistance and inhibit tumor recurrence by specifically suppressing GBM stem-like populations.

PROJECT NARRATIVE Glioblastoma stem-like cancer cells are believed to contribute to poor prognosis and high motility rates of glioma patients. Therefore, our novel strategies to specifically target the glioblastoma stem-like populations for elimination could have great clinical impact.