Targeting the PI3K Pathway in the Brain - Efficacy of a PI3K Inhibitor Optimized to Cross the Blood-Brain Barrier
Menée sur des modèles murins de glioblastome, cette étude évalue l'efficacité antitumorale d'un composé appelé GNE-317, un inhibiteur des voies de signalisation PI3K et mTOR optimisé pour franchir la barrière hémato-encéphalique
Purpose:Glioblastoma(GBM), the most common primary brain tumor in adults, presents a high frequency of alteration in the PI3K pathway. Our objectives were to identify a dual PI3K/mTOR inhibitor optimized to cross the blood-brain barrier(BBB) and characterize its brain penetration, pathway modulation in the brain and efficacy in orthotopic xenograft models of GBM. Experimental Design:Physicochemical properties of PI3K inhibitors were optimized using in silico tools, leading to the identification of GNE-317. This compound was tested in cells over-expressing P-glycoprotein(P-gp) or breast cancer resistance protein(BCRP). Following administration to mice, GNE-317 plasma and brain concentrations were determined, and phosphorylated biomarkers(pAkt, p4EBP1 and pS6) were measured to assess PI3K pathway suppression in the brain. GNE-317 efficacy was evaluated in the U87, GS2 and GBM10 orthotopic models of GBM. Results:GNE-317 was identified as having physicochemical properties predictive of low efflux by P-gp and BCRP. Studies in transfected MDCK cells showed that GNE-317 was not a substrate of either transporter. GNE-317 markedly inhibited the PI3K pathway in mouse brain, causing 40%-90% suppression of the pAkt and pS6 signals up to 6 h post-dose. GNE-317 was efficacious in the U87, GS2 and GBM10 orthotopic models, achieving tumor growth inhibition of 90% and 50%, and survival benefit, respectively. Conclusions:These results indicated that specific optimization of PI3K inhibitors to cross the BBB led to potent suppression of the PI3K pathway in healthy brain. The efficacy of GNE-317 in three intracranial models of GBM suggested that this compound could be effective in the treatment of GBM.