Abstract
BACKGROUND: Glioblastoma (GBM) is one of the most malignant adult brain tumors, with a median survival of only 14 months. The lack of efficient therapies so far can be traced back to issues such as resistance to treatments leading to relapses, novel drugs being unable to penetrate the blood-brain barrier (BBB) and focus on monotherapy approaches in a highly heterogeneous disease. Characterization of the genomic landscape of GBM has revealed that three major signaling pathways are co-abrogated in the majority of patients. We have previously shown proof-of-concept that targeting these pathways (PI3K-mTOR-AKT, MAPK and CDK4/6-RB) using a multi-target combination therapy (MTCT) is a promising way to treat GBM. By looking into a panel of drugs, we are screening for alternative MTCT combinations to identify those most suitable for clinical translation. MATERIAL AND METHODS: From a panel of drugs targeting one these three pathways, we compare each drug's single-agent properties to various combinations. The synergy of the drugs is scored based on proliferation and target inhibition effects. We will establish if candidate drugs are an ABC transporter substrate with transwell assays and how well the drugs can cross the BBB in vivo using ABC transporter knock-out mouse models. Promising MTCT combinations will be further studied using in vivo orthotopic GBM models. RESULTS: We have identified several MTCT combinations that have synergistic effects on target inhibition and cell proliferation. Transwell assays indicate that multiple drugs are to some degree ABC transporter substrates, which might affect the brain penetration of the compounds. Nonetheless, we could identify several candidate drugs targeting the PI3K or MAPK pathway that are relatively weak substrates and for which brain entry is relatively unimpeded. In contrast, finding a candidate with favorable pharmacological properties among the available CDK4/6-RB pathway inhibitors has proven to be more challenging. CONCLUSION: Our results indicate that using an MTCT approach might be promising for treating GBM. Further research is being conducted to find the best possible MTCT combination that can access the tumor through the BBB at sufficient levels to exert its pharmacodynamic effects.