"The overall goal of this proposal is to explore the molecular basis of TRAIL-response in an aggressive brain cancer, Glioblastoma Multiforme (GBM), and identify new reagents that will augment the TRAIL response of GBMs. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL), emerged as a prime candidate for cancer treatment due to its tumor-specificity, however its clinical success is likely limited by the innate or acquired resistance of some tumors to TRAIL. Dr. Bagci-Onder will address whether aberrant expression or activity of apoptotic program components is associated with TRAIL-resistance in GBMs. Specifically, she will address the role of a pro-apoptotic factor, harakiri (HRK), that she found to be significantly repressed in the TRAIL-resistant subpopulation of a primary GBM cell line. The potential role of this hitherto unstudied protein in GBM cell TRAIL response will be uncovered using expression analysis and functional assays in a large panel of GBM lines with varying TRAIL responses. Since multiple components of TRAIL signaling might be misregulated in TRAIL-resistant cells, Dr. Bagci-Onder will generate dual bioluminescent reporter systems of HRK and other TRAIL-associated factors, such as TRAIL receptors DR4/DR5; TRAIL signaling inhibitor proteins Flip, XIAP and Bcl-2 to assess gene expression changes. It is becoming evident that TRAIL-based combinatorial therapies with additional agents that can augment the TRAIL-response of tumors are more efficacious than using TRAIL alone. Using the novel reporter systems, Dr. Bagci-Onder will screen for novel TRAIL-sensitizing agents to identify potential TRAIL-sensitizers among FDA-approved chemicals. The function of these agents will be validated in mouse xenograft GBM models using neural stem cells as vehicles for TRAIL delivery. Together, this project will further the understanding of GBM biology and lead to potential clinical applications."
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