Author ORCID Identifier

https://orcid.org/0000-0002-8885-4531

Date Available

7-1-2025

Year of Publication

2024

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

First Advisor

Dr. Björn Bauer

Abstract

Glioblastoma (GBM) is the deadliest and most common malignant CNS tumor. Despite advances in understanding its biology and the development of targeted therapies, effective treatment options remain limited. As a result, patient survival rates are dismal, with a 5-year survival rate of only 6.8% and an overall survival of less than two years. This poor outcome is partly due to our inability to treat GBM cells that infiltrate the whole brain. Focal treatments like surgery and radiotherapy alone are insufficient due to these invasive tumor cells. Therefore, chemotherapy following resection and irradiation of the primary tumor is essential to eliminate remaining GBM cells.

However, a major challenge with chemotherapy is the presence of blood-brain barrier drug efflux transporters, such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), which hinder anticancer drug entry into the brain. Despite efforts to overcome these transporters, no strategies have extended patient survival or gained FDA approval. Thus, there is an urgent need for approaches that effectively and safely reduce P-gp/BCRP activity to improve anticancer drug uptake throughout the brain. Our laboratory has shown increased expression and activity of efflux transporters, alongside elevated activity of the PI3K/Akt signaling pathway, in the contralateral hemisphere of GBM samples. Based on these observations, we hypothesized that PI3K/Akt inhibition would downregulate drug efflux transporter expression and activity at the blood-brain barrier, increase brain anticancer drug uptake, and extend GBM mouse survival.

To explore this hypothesis, two mouse GBM models, GL261 Red-FLuc and TRP-mCherry-FLuc, were established, characterized, and compared. A fluorescence-guided resection technique was developed to increase the clinical relevance of these models, significantly increasing survival in both models. The effect of the FDA-approved PI3K/Akt inhibitors alpelisib (ALP) and capivasertib (CAP) on drug efflux transporter activity was investigated in ex vivoand in vivo experiments, demonstrating significantly decreased P-gp and BCRP activity with pretreatment. The effect of ALP/CAP pretreatment on the brain uptake and efficacy of the anticancer drug temozolomide, a cornerstone of GBM standard of care, was determined. While temozolomide increased GL261 Red-FLuc mouse survival, pretreatment with ALP/CAP did not enhance temozolomide brain uptake or animal survival. We also examined the effect of ALP/CAP pretreatment on the brain uptake of dasatinib, a tyrosine kinase inhibitor, to assess whether PI3K/Akt inhibition could affect a drug with a lower baseline brain-to-plasma ratio. However, the brain uptake of dasatinib remained unchanged in both treatment groups. These findings underscore the need to optimize drug efflux transporter regulation to improve brain uptake of anticancer drugs.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2024.289

Funding Information

Research reported in this dissertation was supported by

  • National Institute of Neurological Disorders and Stroke of the National Institutes of Health, grant number R01NS107548 (BB) in 2018
  • National Center for Advancing Translational Sciences of the National Institutes of Health, grant number TL1TR001997 (LTR) in 2021
  • Northern Kentucky/Greater Cincinnati UK Alumni Club Fellowship (LTR) in 2020

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Available for download on Tuesday, July 01, 2025

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