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. / Thesis / Doctor of Philosophy (PhD) / Cancer is the leading cause of death in Canada and Glioblastoma Multiforme (GBM) is the most common type of malignant adult brain tumor which is one of the difficult human cancers to treat. In spite of the multi-model therapy including surgery, chemotherapy, and radiation, tumor re-growth and patient relapse are inevitable. A wealth of literature describes the biology of treatment-naïve or primary GBM, but 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). Clinical trials have not shown significant survival advantages for GBM patients, due not only to the lack of biological characterization of the distinct landscape of GBM recurrence, but also due to our poor understanding of the tumor immune microenvironment (TIME), the immune cells surrounding the tumor that may somehow fail to attack it due to GBM cells’ ability to suppress the immune system and evade detection. To understand how GBM cells and the TIME evolve under therapeutic pressure, we performed proteomics analysis on a large cohort of primary-recurrent GBM patient samples, to further understand treatment failure and develop effective and empirical combinatorial poly-therapies for the treatment of therapy-resistant GBM. Besides, in the next part of this study we showed existence of few cells within the tumor, termed brain tumor initiating cells (BTICs) can alone drive tumor growth and cause therapy resistance. To be able to target these population of cells, we identified treatment resistant tumor associated markers (highly expressed cell surface proteins) on these cells and developed novel treatments using a new class of biologics, Dual Antigen T cell Engagers (DATEs), to target these tumor associated markers. DATEs act like a “molecular glue” that specifically binds the patient’s own naturally circulating T-cells (soldier cells of the immune system) to cancer cells. Once bound, the T-cells attack and kill the patient’s cancer cells. In this strategy, the abnormal expression of tumor surface proteins can be used as a handle to drive T cell-mediated cell death. We predict that the dual specific antibodies through this study could be used alone or in combination with existing drugs to treat recurrent GBM.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/27032 |
| Date | January 2021 |
| Creators | Tatari, Nazanin |
| Contributors | Singh, Sheila, Biochemistry and Biomedical Sciences |
| Source Sets | McMaster University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
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