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Eric J. Huselid
B.S., University of California, Davis - 2012
Thesis Advisor: Hatem Sabaawy, M.D., Ph.D.
Graduate Program in Cellular and Molecular Pharmacology
Rutgers Cancer Institute of New Jersey
Multipurpose Room B
Wednesday, March 29, 2017
Glioblastoma (GBM) is the most common and most deadly form of primary brain malignancy. Though the disease rarely metastasizes outside the brain, its invasive nature to the surrounding tissue, resistance to therapy, and very short median survival creates a dire need for new therapeutic agents. Compelling evidence indicates that GBM is a heterogeneous neoplasm composed of bulk tumor cells and a small population of cancer stem cells (CSCs), or tumor-initiating cells (TICs), endowed with self-renewal capacity, high tumorigenic potential, and low proliferation rate. Targeting TICs in GBM represents a promising therapy. BMI1 (B-cell specific MMLV insertion site-1) is a polycomb group protein and member of the chromatin-remodeling complex, PRC1. BMI1 has been shown to regulate stem cell self-renewal in both normal and cancerous tissues, including GBM. We previously identified an effective inhibitor of BMI1 (PTC-209), but due to its poor pharmacokinetic properties, we recently generated a series of compounds with a higher in silico affinity for a potential binding to a pocket within the BMI1’s 5’ UTR. Seventeen compounds were screened for their ability to halt GBM growth. We found that two compounds (IC50 in nM) dramatically reduced GBM TICs survival in vitro by arresting cell cycle progression. Importantly, these compounds reduced the proportion of patient-derived GBM TICs by >20-fold in clonogenic assays. This effect was not observed following treatment with temozolomide, a standard of care GBM drug. An effect on tumor growth was also observed in vivo using mouse PDX model. This study demonstrates the ability to identify agents that specifically eliminate GBM TICs and should be explored as a therapeutic option in a clinical setting.