Glioblastoma (GBM) is the most common and aggressive form of primary brain tumor in adults and is diagnosed more often in males and in females. The current standard of care includes surgical resection, chemotherapy, and radiation therapy, though the tumor often recurs and overall survival for this disease remains low, necessitating the investigation of potential new nodes of treatment. In the search for individualized therapies for GBM, receptor tyrosine kinases (RTKs) have been discovered to mediate different responses and outcomes between male and female patients. This thesis aims to investigate the differential role two RTKs, EGFR and PDGFR, in mediating proliferation, migration, and invasion of GBM cells between males and females. Cell proliferation, migration, and invasion assays were performed using isogenic matched male and female murine GBM cell lines with specific RTK expression mimicking in vivo alterations to their respective oncogenes. Statistical analysis to compare the means of these markers was used to determine discrete trends in male and female cell lines, as well as between males and females with the same mutations. In vitro proliferation, migration, and invasion assays revealed distinct patterns of sex mediated molecular RTK function between males and females. EGFR and PDGFR expression were shown to play different roles in progression between these three metrics. Additionally, the used of an isogenic murine model with sex as a controlled variable allowed male-to-female comparisons, yielding data suggesting some RTKs may attenuate progression in one or more of these benchmarks in one sex more than the other. This study highlights the need for further investigation into the role RTKs play in male versus female GBM progression, which could potentially lead to the creation of new targeted treatments and personalized medicine approaches.

With an estimated 19.3 million cases and nearly 10 million deaths from cancer in a year worldwide, immunotherapies, which stimulate the immune system so that it can attack and kill cancer cells, are of interest. Tumors are produced from the uncontrolled and rapid proliferation of cells in the body. Cancer cells rely heavily on glutamine for proliferation due to its contribution of nitrogen for nucleotides and amino acids. Glutamine enters the tricarboxylic acid (TCA) cycle as α-ketoglutarate via glutaminolysis, in which glutamine is converted into glutamate by the enzyme glutaminase (GLS). Cancer cell proliferation may be limited by using glutaminase inhibitor CB-839. However, immune cells also rely on these metabolic pathways. Thus, a method for restarting the metabolic pathways in the presence of inhibitors is attractive. Succinate, a key metabolite in the TCA cycle, has been shown to stimulate the immune system despite the presence of metabolic inhibitors, such as CB-839. A delivery method of succinate is through microparticles (MPs) or nanoparticles (NPs) which may be coated in polyethylene glycol (PEG) for improved hydrophilicity. Polyethylene glycol succinate (PEGS) MPs were generated and tested in vivo and were shown to reduce tumor growth and prolong mouse survival. With the success in stimulating the immune system with MPs, NPs were investigated for an improved immune response due to their smaller size. These PES NPs were generated in this study. For clinical settings, it is necessary to scale-up the production of particles. Two methods of scale-up were proposed: (1) a combination of multiple small batches into a mixed batch, and (2) a singular, big batch. Size and release properties were compared to a small batch of PES NPs, and it was concluded that the big batch more closely resembled the small batch compared to the mixed batch. Thus, it was concluded that batch-to-batch variability plays a larger role than volume changes when scaling-up. In clinical settings, it is recommended to produce the particles in a big batch rather than a mixed batch.