Author ORCID Identifier

https://orcid.org/0000-0002-6218-4023

Date Available

5-14-2022

Year of Publication

2021

Document Type

Doctoral Dissertation

Degree Name

Doctor of Philosophy (PhD)

College

Pharmacy

Department/School/Program

Pharmaceutical Sciences

Advisor

Dr. Björn Bauer

Abstract

Glioblastoma is one of the deadliest cancers, with a median survival of only one year. Even after aggressive treatment consisting of surgical resection, radiation, and chemotherapy, most glioblastoma patients suffer from tumor recurrence within 6-9 months. One reason for treatment failure of anticancer drugs is the blood-brain barrier that protects the brain by impeding xenobiotic uptake from the blood. To this end, efflux transporters at the human blood-brain barrier, such as P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2), prevent many compounds, including anticancer drugs, from entering the brain. Thus far, approaches to deliver anticancer drugs across the blood-brain barrier have been unsuccessful in clinical trials. Therefore, novel therapeutic strategies are needed to overcome the blood-brain barrier for improved glioblastoma treatment.

Here, I address this need in 3 independent aims:

  1. Elucidate the involvement and cooperation of ABC transporters in anticancer drug transport at the blood-brain barrier
  2. Establish and characterize human glioblastoma models
  3. Evaluate the impact of dual PI3K/Akt inhibition on brain uptake of anticancer drugs

Aim 1: While Abcb1/Abcg2 inhibition improved survival in mouse glioblastoma models, clinical trials had to be terminated due to a lack of efficacy, sparking a discussion that other ABC transporters might be involved in this process. To discern how multiple ABC transporters cooperate in restricting anticancer drug uptake at the blood-brain barrier, I evaluated the effect of several efflux transporters at the blood-brain barrier on the brain level of anticancer drugs using transporter inhibitors or knockout mice.

The results from this study suggest that Abcc4 works in concert with Abcb1/Abcg2 in restricting brain access of the tested anticancer drugs in mice. Further experiments are necessary to confirm this cooperation at the human blood-brain barrier. In part, these findings might provide one possible explanation why therapeutic strategies that solely focus on ABCB1/ABCG2 failed to improve treatment outcomes for glioblastoma patients.

Aim 2: Successful treatment of glioblastoma requires reliable preclinical animal models to evaluate novel approaches and assess their potential therapeutic benefit. While many different glioblastoma models exist, most are not well characterized and only recapitulate a subset of glioblastoma characteristics. Here, I describe and compare two human glioblastoma models, U87-luc2 and U251-FLuc. While both models behave similarly in vitro, they have different in vivo tumor characteristics, such as invasiveness and blood-brain barrier disruption. Together, the two glioblastoma models recapitulate the tumor characteristics of a majority of patients.

Aim 3: Direct transporter inhibition is unsuccessful in improving glioblastoma patient survival due to the low efficacy of inhibitors and adverse effects associated with combination treatment. However, efflux transporter regulation could open a “window-in-time” to allow anticancer drug uptake into the brain. Here, I tested a novel molecular switch approach to overcome Abcb1/Abcg2-mediated efflux at the blood-brain barrier. My data indicate that PI3K/Akt could serve as a molecular switch to transiently turn off Abcb1/Abcg2 at the blood-brain barrier and increase brain levels of anticancer drugs.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2021.111

Funding Information

Funding to JA Schulz:

  • Pharmaceutical Sciences Excellence in Graduate Achievement Fellowship from the University of Kentucky College of Pharmacy (2018-2019)
  • Dr. Joseph F. Pulliam Pilot Award by the University of Kentucky Markey Cancer Center (2020)
  • PhRMA Foundation Pre-Doctoral Fellowship Pharmacology/Toxicology (2020-2021)
  • Travel Funding: UK College of Pharmacy, UK Markey Cancer Center, Blood-Brain Barrier Consortium, and Fluids and Barriers of the CNS

Funding to B Bauer:

  • Grant 1R01NS107548 from the U. S. National Institutes of Health National Institute of Neurological Disorders and Stroke (2018-2021)

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