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Rapid CommunicationAccelerated Communication

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

Laurent Salphati, Sheerin Shahidi-Latham, Cristine Quiason, Kai Barck, Merry Nishimura, Bruno Alicke, Jodie Pang, Richard A. Carano, Alan G. Olivero and Heidi S. Phillips
Drug Metabolism and Disposition July 2014, 42 (7) 1110-1116; DOI: https://doi.org/10.1124/dmd.114.057513
Laurent Salphati
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
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Sheerin Shahidi-Latham
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
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Cristine Quiason
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
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Kai Barck
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
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Merry Nishimura
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
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Bruno Alicke
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
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Jodie Pang
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
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Richard A. Carano
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
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Alan G. Olivero
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
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Heidi S. Phillips
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
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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.

Footnotes

    • Received February 4, 2014.
    • Accepted April 22, 2014.
  • dx.doi.org/10.1124/dmd.114.057513.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (7)
Drug Metabolism and Disposition
Vol. 42, Issue 7
1 Jul 2014
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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
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Rapid CommunicationAccelerated Communication

MALDI Imaging of PI3K Inhibitor Distribution in Brain Tumors

Laurent Salphati, Sheerin Shahidi-Latham, Cristine Quiason, Kai Barck, Merry Nishimura, Bruno Alicke, Jodie Pang, Richard A. Carano, Alan G. Olivero and Heidi S. Phillips
Drug Metabolism and Disposition July 1, 2014, 42 (7) 1110-1116; DOI: https://doi.org/10.1124/dmd.114.057513

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Rapid CommunicationAccelerated Communication

MALDI Imaging of PI3K Inhibitor Distribution in Brain Tumors

Laurent Salphati, Sheerin Shahidi-Latham, Cristine Quiason, Kai Barck, Merry Nishimura, Bruno Alicke, Jodie Pang, Richard A. Carano, Alan G. Olivero and Heidi S. Phillips
Drug Metabolism and Disposition July 1, 2014, 42 (7) 1110-1116; DOI: https://doi.org/10.1124/dmd.114.057513
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