A Novel Strategy to Overcome the P-gp/BCRP Drug Efflux System at the Blood-Brain Barrier to Improve Brain Uptake of CNS Therapeutics

The blood-brain barrier is a primary obstacle for effective anticancer drug therapy of patients with glioblastoma multiforme (GBM). On a molecular level, failure of anticancer drug treatment is largely due to the P-gp/BCRP drug efflux system at the blood-brain barrier. There is a fundamental gap in understanding how the P-gp/BCRP drug efflux system is regulated at the blood-brain barrier in GBM. This gap in the knowledge base represents a significant clinical problem since it prevents development of effective approaches that can be applied to overcome the P-gp/BCRP drug efflux system to allow sufficient uptake of anticancer therapeutics into the brain. The long-term goal of the investigator is to identify molecular mechanisms that control blood-brain barrier function and can be targeted to improve brain uptake of anticancer drugs. The overall objective of this application is to develop an effective therapeutic strategy to overcome P-gp/BCRP-mediated anticancer drug efflux and prolong survival in mice with GBM. Based on preliminary data the central hypothesis is that inhibiting PI3K/Akt activity will lead to decreased P-gp/BCRP levels, which in turn will result in increased brain uptake of anticancer drugs, thereby reducing tumor size and prolonging GBM mouse survival. The rationale for this research is that its successful completion is expected to provide a solid, evidence-based scientific framework for translating our strategy into a phase I clinical trial. Based on strong preliminary data, this hypothesis will be tested by pursuing three specific aims: 1) Determine the mechanism(s) by which GBM induces P-gp/BCRP overexpression; 2) Identify pathways that regulate P-gp/BCRP at the human blood-brain barrier; and 3) Develop a therapeutic strategy to increase anticancer drug brain uptake in GBM mice. Under the first aim, mechanistic steps involved in GBM-induced overexpression of blood-brain barrier P-gp/BCRP will be assessed in isolated mouse brain capillaries. The impact of blocking these steps on brain uptake of anticancer drugs in GBM-bearing mice will be determined. Under the second aim, P-gp/BCRP regulation by the PTEN/PI3K/Akt/mTOR pathway will be determined in brain capillaries from healthy individuals and from GBM patients. Under the third aim, the therapeutic benefit of combining PI3K/Akt inhibitors with anticancer drugs to reduce P-gp/BCRP levels with the goal of improving brain uptake of anticancer drugs and prolonging survival will be assessed in three different GBM models. The proposed research is innovative, in the applicant's opinion, because it represents a new and substantive departure from the status quo by shifting the focus to a molecular switch-based approach to overcome P-gp/BCRP-mediated drug efflux at the blood-brain barrier. The proposed research is significant because it is expected that the new knowledge may have broad translational importance in the treatment of patients with GBM and potentially other brain tumors as well. Ultimately, such knowledge has the potential to help improve drug brain uptake strategies in other CNS disorders since many therapeutically used CNS drugs are Pgp/ BCRP substrates.