Development of a multi-target drug combination targeting three major proliferation pathways in glioblastoma

Abstract

Glioblastoma (GBM) is one of the most prevalent and aggressive brain tumors in adults, with limited treatment options and poor survival outcomes. The lack of effective therapies stems from resistance mechanisms, the failure of drugs to cross the blood-brain barrier, and a focus on monotherapy in a highly heterogeneous disease. Characterization of the genomic landscape of GBM has revealed that three signaling pathways are commonly dysregulated in the majority of patients. Based on this information, we developed a multi-target combination therapy (MTCT) that targets the PI3K-mTOR-AKT, MAPK, and CDK4/6-RB pathways. Through in vitro screenings, we identified several combinations of inhibitors that demonstrate synergy, significantly decreasing cell proliferation and inducing targeted inhibition of all three pathways. In a proof-of-concept study, we previously demonstrated that targeting these pathways in Abcb1a/b;Abcg2−/− mice, bearing intracranial GBM tumors, significantly reduced tumor growth. These mice lack ABCB1 and ABCG2 efflux transporters that actively pump drugs out of the brain. In this study, we showed that in a case where the drugs would not be substrates to these transporters, the treatment works. Now our focus lies in finding the most promising combination for clinical use by selecting drugs that can pass the BBB with the transporters present at pharmacologically active levels. We conducted studies in tumor-free animals to establish dosing regimens that yield clinically relevant pharmacokinetic profiles, which we achieved by delivering the drugs through the drinking water. Currently, we are performing intracranial GBM tumor models to investigate the pharmacodynamics of the treatment, focusing on its effects on tumor growth, survival, and targeted inhibition in clinically relevant GBM models.