Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Master of Science

Program

Neuroscience

Collaborative Specialization

Molecular Imaging

Supervisor

Ronald, John A.

2nd Supervisor

Hebb, Matthew O

Abstract

Glioblastoma (GBM) is a devastating incurable malignant brain cancer in need of new treatments. We have begun to investigate the feasibility of a primary adult cell type (Brain-Derived Progenitor Cells, BDPCs) as a novel therapeutic delivery system to GBM. Our objective was to track the viability of BDPCs after intratumoral infusion into syngeneic orthotopic rat GBM tumours using non-invasive bioluminescence imaging (BLI). We hypothesize rat BDPCs will survive greater than 1 week following infusion into orthotopic F98 GBM tumors. BDPCs harvested from the cortex of adult Fischer rats were expanded in culture then engineered to co-express firefly Luciferase for BLI as well as the fluorescence protein tdTomato. In vitro assays displayed consistent lentiviral engineering of transgenes as well as statistically significant GBM-homing by BDPCs (p < 0.01). All animals showed in vivo BLI signal until the study’s endpoint, confirming viable BDPCs were still present. Histological examination revealed small numbers of fluorescent BDPCs at the tumours’ invading edges in frozen coronal sections.

Summary for Lay Audience

Glioblastoma (GBM) is an aggressive type of brain cancer that currently has no cure. Despite a multidisciplinary standard of treatment, fewer than 10% of patients survive 5 years post-diagnosis. However, recent research has shown that certain stem cells may be used as a promising therapy for treating GBM. The aim of this work was to investigate the potential of Brain-Derived Progenitor Cells (BDPCs) for delivering therapeutic agents to GBM tumours. BDPCs can be safely obtained from surgical patients, then cultured and engineered in the research laboratory. By engineering BDPCs to emit light under specific conditions, we hypothesized that we would be able to track their viability inside of a rat tumour. The results of this experiment would inform downstream experiments aimed at determining the optimal conditions necessary for achieving BDPCs’ therapeutic delivery to GBM. The study used a combination of in vitro and in vivo experiments to test the feasibility of BDPCs as therapeutic delivery system for GBM. In vitro experiments involved growing BDPCs in special culture chambers and testing their ability to migrate towards GBM cells. In vivo experiments involved injecting engineered BDPCs into rats’ GBM tumours to see if they would remain viable and for how long. The results of the study showed that both human and rat BDPCs did significantly migrate towards their respective glioblastoma cells in vitro. Furthermore, BDPCs engineered with molecular imaging transgenes remained viable in our brain cancer model by BLI signal until study endpoint. This manuscript offers promising evidence that BPDC-based therapy could be a valuable tool for treating GBM in the future. By using these specialized cells to deliver targeted therapies, we hope to improve treatment outcomes and ultimately find a cure for this devastating disease.

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