Glioblastoma is the most commonly diagnosed central nervous system primary malignancy and it is considered a terminal diagnosis with few treatment options available. Glioblastoma tumors frequently develop treatment resistance due in part to their highly heterogenic nature. The heterogeneity of glioblastoma is partially attributed to the presence of glioma stem-like cells (GSC), which are highly invasive and resistant to chemotherapy and irradiation treatments. Signaling of the receptor tyrosine kinase MET is a known regulator of GSC. Glioblastoma patients have an increasingly poor prognosis that corresponds with increasing MET expression. Both GSC and MET are known to contribute to treatment resistance in glioblastoma and several MET alterations have been observed in glioblastoma.
In these studies, we investigated MET alterations that are commonly found in glioblastoma. Using patient-derived xenograft (PDX) lines, the MET alterations were characterized and confirmed to be MET positive, MET amplified, or harbor a PTPRZ1-MET fusion. We also included a MET null glioblastoma PDX line. The PDX lines demonstrated markers for GSC potential with all showing neurosphere formation, the ability to initiate tumor growth in immune-compromised mice, and expression of GSC markers GFAP, Sox2, and nestin. The MET alterations were further examined by examining tyrosine kinase inhibitors' effect on viability and MET signaling. Oncogene addiction through MET amplification was found to have the best response to inhibition. The MET fusion bearing line demonstrated less sensitivity to inhibition than has been shown in other studies, indicating a need for further research into co-mutations that increase sensitivity to MET inhibition. We also investigated the efficacy of novel MET-targeting chimeric antigen receptor T cells (MET.CART cells). The MET.CART cells were able to specifically target and successfully kill MET-expressing glioblastoma cells. Together these results imply the need for more personalized treatment of glioblastoma based on the molecular biology of the tumor.
| Identifer | oai:union.ndltd.org:ETSU/oai:dc.etsu.edu:etd-5778 |
| Date | 01 August 2023 |
| Creators | Musket, Anna |
| Publisher | Digital Commons @ East Tennessee State University |
| Source Sets | East Tennessee State University |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | Electronic Theses and Dissertations |
| Rights | Copyright by the authors. |
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