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Bilal, Nida

University of British Columbia

Advanced central nervous system (CNS) cancer is a largely terminal disease with low survival rates that gets progressively worse with neurological symptoms affecting normal function and quality of life. Patients are often excluded from clinical trials because the blood-brain barrier limits penetration of most drugs to the brain. Only 2% of all cancer drugs have been approved for treatment. The overarching objective of this research was to develop a novel RNA therapeutic to treat high-grade gliomas, particularly Glioblastoma Multiforme (GBM). This was designed to target the p53 pathway. p53 is a tumour suppressor and the most frequently mutated gene in many cancers. Starting with a bioinformatics study that identified glioma-relevant targets in the p53 pathway, subsequent in vitro cell viability studies were conducted to iteratively assess cytotoxicity with single and multiple agent gene targets. This was to discover a multi-agent RNA combination with the highest cytotoxic synergistic efficacy in GBM cells and relative non-toxicity in non-malignant brain cells. Additionally, p53 expression of the RNA drug candidates was measured to validate activation of p53 pathway. Lastly, an RNA-Seq study was conducted to further investigate transcriptomic effects of the discovered RNA combination compared to p53-mRNA treatment. At least 33% more apoptosis and dose-relative response was triggered through a discovered triple-agent siRNA/ mRNA combination treatment compared to single-agent RNA drugs. This treatment also induced p53 expression indicating a p53-based mechanism. In non-malignant neurons, combination treatment showed higher cell viability versus untreated cells, suggesting relative non-toxicity. While single-agent p53-mRNA treatments revealed a primarily p53-based mechanism, combination treatments, additionally also indicated modulation of other pathways in differential gene/ pathway analysis, suggesting unique pharmacodynamics based on treatment and p53 mutation status. Cell proliferation biomarker, ki-67 expression was significantly downregulated only with RNA combination therapy. This novel RNA combination discovery signifies a potentially efficacious therapy that selectively targets cancer cells and activates the broader p53 network and induces programmed cell death for a comprehensive anti-tumour response. This is intended to address the unmet need of improving overall survival in GBM patients and other cancers where p53 has a high mutation rate, such as lung and ovarian cancers.

Text

2023-09-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/79701

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/