title: 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.
abstract: Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and the limited available treatment options have not meaningfully impacted patient survival in the past decades. Such poor outcomes can be at least partly attributed to the inability of most drugs tested to cross the blood-brain barrier and reach all areas of the glioma. The objectives of these studies were to visualize and compare by matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry the brain and tumor distribution of the phosphatidylinositol 3-kinase (PI3K) inhibitors pictilisib (GDC-0941, 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine) and GNE-317 [5-(6-(3-methoxyoxetan-3-yl)-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine] in U87 and GS2 orthotopic models of GBM, models that exhibit differing blood-brain barrier characteristics. Following administration to tumor-bearing mice, pictilisib was readily detected within tumors of the contrast-enhancing U87 model whereas it was not located in tumors of the nonenhancing GS2 model. In both GBM models, pictilisib was not detected in the healthy brain. In contrast, GNE-317 was uniformly distributed throughout the brain in the U87 and GS2 models. MALDI imaging revealed also that the pictilisib signal varied regionally by up to 6-fold within the U87 tumors whereas GNE-317 intratumor levels were more homogeneous. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analyses of the nontumored half of the brain showed pictilisib had brain-to-plasma ratios lower than 0.03 whereas they were greater than 1 for GNE-317, in agreement with their brain penetration properties. These results in orthotopic models representing either the contrast-enhancing or invasive areas of GBM clearly demonstrate the need for whole-brain distribution to potentially achieve long-term efficacy in GBM.
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S-L., C.Q., J.P.), Biomedical Imaging (K.B., R.A.C.), Cancer Signaling and Translational Oncology (M.N., B.A., H.S.P.), and Chemistry (A.G.O.), Genentech, Inc., South San Francisco, California salphati.laurent@gene.com.
authors.forename: Laurent
authors.initials: L
authors.lastname: Salphati
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S-L., C.Q., J.P.), Biomedical Imaging (K.B., R.A.C.), Cancer Signaling and Translational Oncology (M.N., B.A., H.S.P.), and Chemistry (A.G.O.), Genentech, Inc., South San Francisco, California.
authors.forename: Sheerin
authors.initials: S
authors.lastname: Shahidi-Latham
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S-L., C.Q., J.P.), Biomedical Imaging (K.B., R.A.C.), Cancer Signaling and Translational Oncology (M.N., B.A., H.S.P.), and Chemistry (A.G.O.), Genentech, Inc., South San Francisco, California.
authors.forename: Cristine
authors.initials: C
authors.lastname: Quiason
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S-L., C.Q., J.P.), Biomedical Imaging (K.B., R.A.C.), Cancer Signaling and Translational Oncology (M.N., B.A., H.S.P.), and Chemistry (A.G.O.), Genentech, Inc., South San Francisco, California.
authors.forename: Kai
authors.initials: K
authors.lastname: Barck
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S-L., C.Q., J.P.), Biomedical Imaging (K.B., R.A.C.), Cancer Signaling and Translational Oncology (M.N., B.A., H.S.P.), and Chemistry (A.G.O.), Genentech, Inc., South San Francisco, California.
authors.forename: Merry
authors.initials: M
authors.lastname: Nishimura
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S-L., C.Q., J.P.), Biomedical Imaging (K.B., R.A.C.), Cancer Signaling and Translational Oncology (M.N., B.A., H.S.P.), and Chemistry (A.G.O.), Genentech, Inc., South San Francisco, California.
authors.forename: Bruno
authors.initials: B
authors.lastname: Alicke
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S-L., C.Q., J.P.), Biomedical Imaging (K.B., R.A.C.), Cancer Signaling and Translational Oncology (M.N., B.A., H.S.P.), and Chemistry (A.G.O.), Genentech, Inc., South San Francisco, California.
authors.forename: Jodie
authors.initials: J
authors.lastname: Pang
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S-L., C.Q., J.P.), Biomedical Imaging (K.B., R.A.C.), Cancer Signaling and Translational Oncology (M.N., B.A., H.S.P.), and Chemistry (A.G.O.), Genentech, Inc., South San Francisco, California.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Carano
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S-L., C.Q., J.P.), Biomedical Imaging (K.B., R.A.C.), Cancer Signaling and Translational Oncology (M.N., B.A., H.S.P.), and Chemistry (A.G.O.), Genentech, Inc., South San Francisco, California.
authors.forename: Alan G
authors.initials: AG
authors.lastname: Olivero
authors.affiliation: Departments of Drug Metabolism and Pharmacokinetics (L.S., S.S-L., C.Q., J.P.), Biomedical Imaging (K.B., R.A.C.), Cancer Signaling and Translational Oncology (M.N., B.A., H.S.P.), and Chemistry (A.G.O.), Genentech, Inc., South San Francisco, California.
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Phillips
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D007191:Indazoles / Q000493:pharmacokinetics* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines / Q000493:pharmacokinetics* / Q000494:pharmacology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods*; D013449:Sulfonamides / Q000493:pharmacokinetics* / Q000494:pharmacology; D013876:Thiophenes / Q000493:pharmacokinetics* / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; D004791:Enzyme Inhibitors; C580635:GNE-317; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D013876:Thiophenes