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Title: | Identification of Novel Therapeutic Targets and Rational Development of Immunotherapeutics for Recurrent Glioblastoma |
Other Titles: | IDENTIFICATION, VALIDATION, AND IMMUNOTHERAPEUTIC TARGETING OF NOVEL TUMOR-ASSOCIATED ANTIGENS FOR TREATMENT-REFRACTORY GLIOBLASTOMA |
Authors: | Tatari, Nazanin |
Advisor: | Singh, Sheila |
Department: | Biochemistry and Biomedical Sciences |
Keywords: | Brain tumor;Immunotherapy |
Publication Date: | 2021 |
Abstract: | Glioblastoma (GBM) is the most common and aggressive brain tumor in adults which is characterized by extensive cellular and genetic heterogeneity. Even with surgery, chemotherapy with temozolomide, and radiation, tumor re-growth and patient relapse are inevitable. The extensive inter- and intra-tumoral heterogeneity (ITH) of recurrent GBM emerges from dysregulation at multiple -omic levels of the tumor. ITH exits at the cellular level due to a small subpopulation of chemo- and radio-resistant cells, called brain tumor initiating cells, which may drive GBM treatment resistance. Although a wealth of literature describes the biology of primary GBM (pGBM), we currently lack an understanding of how GBM evolves through therapy to become a very different tumor at recurrence, which may explain why therapies against primary GBM fail to work in recurrent GBM (rGBM). Thus, understanding the tumor evolution from a multi-omic perspective is critical for the development of effective therapeutic approaches. The current work focuses on identification and validation of novel predictive and prognostic biomarkers for rGBM using proteomics analysis on a large cohort of patientmatched pGBM-rGBM samples. This work allowed for detailed characterization of rGBM and its cognate TIME toward a better understanding of the molecular players driving recurrence which can be further used for instructing effective targeted and personalized therapies for the treatment of therapy-resistant GBM. In another part, we developed a novel immunotherapeutic modality called dual antigen T cell engager, to target Carbonic Anhydrase 9, a highly enriched hypoxia-inducible enzyme in GBM. We demonstrated that this immunotherapeutic strategy which allows for targeting tumor cells while recruiting and triggering T cells through simultaneously, is highly effective in eliminating tumor cells and can be a complementary component of combinatorial therapy for GBM patients. Altogether, this study provided key data for instructing novel and rational combinatorial polytherapeutic approaches for the treatment of therapy-resistant GBM. |
URI: | http://hdl.handle.net/11375/27032 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Tatari_Nazanin_2021September_PhD.pdf | 5.02 MB | Adobe PDF | View/Open |
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