Honors College Thesis

 

Fighting the global cancer burden: a promising molecular based cancer therapy Public

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https://ir.library.oregonstate.edu/concern/honors_college_theses/05741t827

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  • Glioblastoma, which occurs in adults primarily between ages of 40 to 70 years and accounts for 15% of all brain tumors, is a devastating diagnosis with a median survival rate of less than a year. Invasiveness of glioblastoma cells significantly reduces the effectiveness of current treatments, highlighting the importance of understanding the characteristics of the invasive population. In glioblastoma cells, influxes of Ca²⁺ activate Ca²⁺-dependent signaling pathways, which promote cell invasion. Calpain 2 is a calcium dependent protease. Previous studies have shown a 90% reduction of glioblastoma cells invasiveness by knocking down calpain 2, demonstrating calpain 2 expression is required for glioblastoma cell invasion. Understanding the mechanism through which calpain 2 promotes cell invasion may lead to an effective treatment for glioblastoma. In collaboration with Dr. Issac Donkor, we are screening novel synthetic calpain 2 inhibitors for the ability to inhibit glioblastoma cell invasion in culture. Four synthetic calpain 2 inhibitors were examined. Initial screening identified one calpain 2 inhibitor (LJ351) that blocked cell invasion at concentrations of 50-100 μM. Our morphology assay showed that LJ351 does not have an effect on cell morphology. We are currently in the process of testing these inhibitors in the zebrafish xenograft model, which is a rapid and inexpensive method for measuring glioblastoma invasion in a dynamic brain microenvironment. Use of the xCELLigence system combined with the zebrafish xenograft model provides an efficient approach for identifying calpain 2 inhibitors with the potential to inhibit tumor cell invasion in glioblastoma. Identifying molecular based treatment can reduce the global burden for cancer. At the same time, the socioeconomic differential in cancer survival should also be considered and addressed.
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