About GSBS   |  FAQ  |  Job Opportunities  |  Search UMDNJ
     




Developing Novel Pharmacological Inhibitors to Target BMI1 in Glioblastoma

by
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
New Brunswick

Wednesday, March 29, 2017
1:00 p.m.


Abstract

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 BMI1s 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.


Return to Dissertation list

 

Newark Campus - Piscataway Campus - Stratford Campus
About GSBS - FAQ - Job Opportunities - Search UMDNJ