title: Targeting the PI3K pathway in the brain--efficacy of a PI3K inhibitor optimized to cross the blood-brain barrier.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Genentech Inc, South San Francisco, California 94080, USA. salphati.laurent@gene.com
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffron
authors.forename: Bruno
authors.initials: B
authors.lastname: Alicke
authors.forename: Merry
authors.initials: M
authors.lastname: Nishimura
authors.forename: Kai
authors.initials: K
authors.lastname: Barck
authors.forename: Richard A
authors.initials: RA
authors.lastname: Carano
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cheong
authors.forename: Kyle A
authors.initials: KA
authors.lastname: Edgar
authors.forename: Joan
authors.initials: J
authors.lastname: Greve
authors.forename: Samir
authors.initials: S
authors.lastname: Kharbanda
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Shari
authors.initials: S
authors.lastname: Lau
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Lee
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.forename: Emile G
authors.initials: EG
authors.lastname: Plise
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Pokorny
authors.forename: Hani Bou
authors.initials: HB
authors.lastname: Reslan
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Wallin
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Zhang
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.forename: Alan G
authors.initials: AG
authors.lastname: Olivero
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Phillips
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002199:Capillary Permeability; D002460:Cell Line; D002463:Cell Membrane Permeability; D004285:Dogs; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D013876:Thiophenes / Q000493:pharmacokinetics* / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C580635:GNE-317; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013876:Thiophenes; D051057:Proto-Oncogene Proteins c-akt