Julia A. Schulz

Glioblastoma is the most common and most devastating human brain cancer. On average, patients survive for only one year after diagnosis. Therefore, glioblastoma is also called “the terminator.” One reason for the 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 blood-brain barrier, such as P-glycoprotein and Breast Cancer Resistance Protein, prevent a myriad of 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 to overcome the blood-brain barrier to improve glioblastoma treatment are urgently needed. This project hypothesizes that downregulating the efflux transporters P-glycoprotein and Breast Cancer Resistance Protein at the blood-brain barrier through dual PI3K/Akt inhibition opens a “window-in-time” that allows anticancer drugs to enter the brain. This research will determine the mechanism through which PI3K/Akt regulates efflux transporters at the blood-brain barrier. Additionally, this therapeutic approach will be tested in a mouse glioblastoma model. It is expected that PI3K/Akt inhibition will lead to increased anticancer drug brain levels, which will result in reduced tumor size and prolonged survival in a mouse glioblastoma model. This study will serve as a first step toward developing a new therapeutic strategy for glioblastoma and is expected to positively impact the treatment, survival and well-being of glioblastoma patients.