Targeting the PI3K Pathway in the Brain—Efficacy of a PI3K Inhibitor Optimized to Cross the Blood–Brain Barrier

Abstract

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 overexpressing 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% to 90% suppression of the pAkt and pS6 signals up to 6-hour postdose. 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 3 intracranial models of GBM suggested that this compound could be effective in the treatment of GBM.

Distribution of the Phosphatidylinositol 3-Kinase Inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 Intracranial Glioblastoma Models—Assessment by Matrix-Assisted Laser Desorption Ionization Imaging

“…Doses were selected based on previous pharmacokinetic and efficacy studies. Plasma concentrations of the two compounds measured 1 and 6 hours after the dose (Tables 1 and 2) were consistent with our previous studies (Salphati et al, 2010;Salphati et al, 2012). Brain levels obtained from the nontumored hemisphere after tissue homogenization confirmed the brain penetration potential of each compound, with total brain-to-plasma ratios lower than 0.03 for pictilisib and greater than 1 for GNE-317 (Tables 1 and 2).…”

Genetic and pharmacological reactivation of the mammalian inactive X chromosome

“…4B and Fig. S5B), a PI3K inhibitor specifically designed to cross the bloodbrain barrier (27). As expected, with all three inhibitors the majority of cells contained two Mecp2 RNA FISH signals and lacked a detectable Xist cloud.…”

Brain Exposure of Two Selective Dual CDK4 and CDK6 Inhibitors and the Antitumor Activity of CDK4 and CDK6 Inhibition in Combination with Temozolomide in an Intracranial Glioblastoma Xenograft

“…U87MG tumors also express P-gp and BCRP (Carcaboso et al, 2010) consistent with clinical findings in gliomas (Fattori et al, 2007), but the functional significance of this expression can be questioned. For example, GDC-0941[2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine], a P-gp and BCRP substrate, was efficacious in the orthotopic U87MG model, reducing tumor volume by .60% despite limited brain penetration in the presence of an intact BBB (Salphati et al, 2012). Some of these criticisms about the translatability of the U87MG model were acknowledged by demonstrating activity in this model, which is typically used as a prerequisite for clinical testing.…”