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

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.

[1]  T. Cloughesy,et al.  Glioblastoma: from molecular pathology to targeted treatment. , 2014, Annual review of pathology.

[2]  D. Haussler,et al.  The Somatic Genomic Landscape of Glioblastoma , 2013, Cell.

[3]  M. Vogelbaum,et al.  Function of the Blood-Brain Barrier and Restriction of Drug Delivery to Invasive Glioma Cells: Findings in an Orthotopic Rat Xenograft Model of Glioma , 2013, Drug Metabolism and Disposition.

[4]  J. Barnholtz-Sloan,et al.  CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. , 2012, Neuro-oncology.

[5]  J. Sarkaria,et al.  Targeting the PI3K Pathway in the Brain—Efficacy of a PI3K Inhibitor Optimized to Cross the Blood–Brain Barrier , 2012, Clinical Cancer Research.

[6]  S. Sideris,et al.  The design and identification of brain penetrant inhibitors of phosphoinositide 3-kinase α. , 2012, Journal of medicinal chemistry.

[7]  S. Al-Sarraj,et al.  Receptor tyrosine kinase genes amplified in glioblastoma exhibit a mutual exclusivity in variable proportions reflective of individual tumor heterogeneity. , 2012, Cancer research.

[8]  J. Schellens,et al.  Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP , 2012, Investigational New Drugs.

[9]  J. Polli,et al.  Lapatinib Distribution in HER2 Overexpressing Experimental Brain Metastases of Breast Cancer , 2012, Pharmaceutical Research.

[10]  E. Nexo,et al.  Erlotinib Accumulation in Brain Metastases from Non-small Cell Lung Cancer: Visualization by Positron Emission Tomography in a Patient Harboring a Mutation in the Epidermal Growth Factor Receptor , 2011, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[11]  W. Cavenee,et al.  Heterogeneity maintenance in glioblastoma: a social network. , 2011, Cancer research.

[12]  Sagar Agarwal,et al.  Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain , 2011, Expert Reviews in Molecular Medicine.

[13]  S. Grossman,et al.  Tissue concentration of systemically administered antineoplastic agents in human brain tumors , 2011, Journal of Neuro-Oncology.

[14]  P. Steeg,et al.  Heterogeneous Blood–Tumor Barrier Permeability Determines Drug Efficacy in Experimental Brain Metastases of Breast Cancer , 2010, Clinical Cancer Research.

[15]  Leslie B. Lee,et al.  Role of P-Glycoprotein and Breast Cancer Resistance Protein-1 in the Brain Penetration and Brain Pharmacodynamic Activity of the Novel Phosphatidylinositol 3-Kinase Inhibitor GDC-0941 , 2010, Drug Metabolism and Disposition.

[16]  Sagar Agarwal,et al.  Distribution of Gefitinib to the Brain Is Limited by P-glycoprotein (ABCB1) and Breast Cancer Resistance Protein (ABCG2)-Mediated Active Efflux , 2010, Journal of Pharmacology and Experimental Therapeutics.

[17]  T. Cloughesy,et al.  mTOR signaling in glioblastoma: lessons learned from bench to bedside , 2010, Neuro-oncology.

[18]  Eric C. Holland,et al.  Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma , 2010, Nature Reviews Cancer.

[19]  G. Gallia,et al.  Intratumoral concentrations of imatinib after oral administration in patients with glioblastoma multiforme , 2010, Journal of Neuro-Oncology.

[20]  Barry Merriman,et al.  U87MG Decoded: The Genomic Sequence of a Cytogenetically Aberrant Human Cancer Cell Line , 2010, PLoS genetics.

[21]  D. Bigner,et al.  Glioblastoma multiforme: a review of where we have been and where we are going , 2009, Expert opinion on investigational drugs.

[22]  T. Cloughesy,et al.  Targeted therapy for malignant glioma patients: Lessons learned and the road ahead , 2009, Neurotherapeutics.

[23]  Walter A. Korfmacher,et al.  MALDI-tandem mass spectrometry imaging of astemizole and its primary metabolite in rat brain sections. , 2009, Bioanalysis.

[24]  R. Farinotti,et al.  Disposition of everolimus in mdr1a-/1b- mice and after a pre-treatment of lapatinib in Swiss mice. , 2009, Biochemical pharmacology.

[25]  Joseph W. Polli,et al.  An Unexpected Synergist Role of P-Glycoprotein and Breast Cancer Resistance Protein on the Central Nervous System Penetration of the Tyrosine Kinase Inhibitor Lapatinib (N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine; GW572016) , 2009, Drug Metabolism and Disposition.

[26]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[27]  M. Westphal,et al.  Glioblastoma-derived stem cell-enriched cultures form distinct subgroups according to molecular and phenotypic criteria , 2008, Oncogene.

[28]  K. Frei,et al.  Gefitinib concentrations in human glioblastoma tissue , 2007, Journal of Neuro-Oncology.

[29]  M. Desai,et al.  Randomized Study of Paclitaxel and Tamoxifen Deposition into Human Brain Tumors: Implications for the Treatment of Metastatic Brain Tumors , 2006, Clinical Cancer Research.

[30]  J. Beijnen,et al.  Blood–brain barrier and chemotherapeutic treatment of brain tumors , 2006, Expert review of neurotherapeutics.

[31]  Thomas D. Wu,et al.  Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. , 2006, Cancer cell.

[32]  Dean Billheimer,et al.  Integrating histology and imaging mass spectrometry. , 2004, Analytical chemistry.

[33]  W. Daniel,et al.  Intracellular distribution of psychotropic drugs in the grey and white matter of the brain: the role of lysosomal trapping , 2001, British journal of pharmacology.

[34]  J. Dichgans,et al.  Predicting chemoresistance in human malignant glioma cells: The role of molecular genetic analyses , 1998, International journal of cancer.