Fellowship for Julia Schulz: Dual PI3K/Akt Inhibition to Overcome Blood-Brain Barrier P-gp and BCRP: A New Strategy to Improve Glioblastoma Therapy

Glioblastoma multiforme (GBM) is one of the most devastating human cancers; median survival is only 15-23 months. One reason for treatment failure is expression of drug efflux transporters Pglycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) at the blood-brain barrier that limit brain uptake of anticancer drugs. Since there are currently no viable options to overcome Pgp/ BCRP efflux, there is a need for novel approaches. The central hypothesis of this proposal is that PI3K/Akt inhibition decreases P-gp/BCRP expression and activity at the blood-brain barrier which increases brain levels of anticancer drugs and in turn reduces tumor size and prolongs survival in a mouse GBM model. To test this hypothesis, we will determine the effect of PI3K/Akt inhibition on brain uptake of anticancer drugs. Additionally, we will determine the effect of PI3K/Akt inhibition on GBM mouse survival. Successful completion of this research is expected to provide 1) better insight into the regulation of P-gp/BCRP expression and activity at the blood-brain barrier and 2) proof-of-concept of a novel strategy to improve GBM therapy by increasing brain uptake of anticancer drugs. In addition, this study will serve as a first step towards translating the proposed therapeutic strategy into clinical practice. I expect this research will have a positive impact on the treatment of GBM patients, their survival and overall well-being.