title: Convection-enhanced delivery of etoposide is effective against murine proneural glioblastoma.
abstract: BACKGROUND
  Glioblastoma subtypes have been defined based on transcriptional profiling, yet personalized care based on molecular classification remains unexploited. Topoisomerase II (TOP2) contributes to the transcriptional signature of the proneural glioma subtype. Thus, we targeted TOP2 pharmacologically with etoposide in proneural glioma models.
  
  
  METHODS
  TOP2 gene expression was evaluated in mouse platelet derived growth factor (PDGF)(+)phosphatase and tensin homolog (PTEN)(-/-)p53(-/-) and PDGF(+)PTEN(-/-) proneural gliomas and cell lines, as well as human glioblastoma from The Cancer Genome Atlas. Correlation between TOP2 transcript levels and etoposide susceptibility was investigated in 139 human cancer cell lines from the Cancer Cell Line Encyclopedia public dataset and in mouse proneural glioma cell lines. Convection-enhanced delivery (CED) of etoposide was tested on cell-based PDGF(+)PTEN(-/-)p53(-/-) and retroviral-based PDGF(+)PTEN(-/-) mouse proneural glioma models.
  
  
  RESULTS
  TOP2 expression was significantly higher in human proneural glioblastoma and in mouse proneural tumors at early as well as late stages of development compared with normal brain. TOP2B transcript correlated with susceptibility to etoposide in mouse proneural cell lines and in 139 human cancer cell lines from the Cancer Cell Line Encyclopedia. Intracranial etoposide CED treatment (680 μM) was well tolerated by mice and led to a significant survival benefit in the PDGF(+)PTEN(-/-)p53(-/-) glioma model. Moreover, etoposide CED treatment at 80 μM but not 4 μM led to a significant survival advantage in the PDGF(+)PTEN(-/-) glioma model.
  
  
  CONCLUSIONS
  TOP2 is highly expressed in proneural gliomas, rendering its pharmacological targeting by intratumoral administration of etoposide by CED effective on murine proneural gliomas. We provide evidence supporting clinical testing of CED of etoposide with a molecular-based patient selection approach.
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Adam M
authors.initials: AM
authors.lastname: Sonabend
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Carminucci
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Benjamin
authors.initials: B
authors.lastname: Amendolara
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Mukesh
authors.initials: M
authors.lastname: Bansal
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Richard
authors.initials: R
authors.lastname: Leung
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Liang
authors.initials: L
authors.lastname: Lei
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Ronald
authors.initials: R
authors.lastname: Realubit
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Hai
authors.initials: H
authors.lastname: Li
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Charles
authors.initials: C
authors.lastname: Karan
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Jonathan
authors.initials: J
authors.lastname: Yun
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Christopher
authors.initials: C
authors.lastname: Showers
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Robert
authors.initials: R
authors.lastname: Rothcock
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Jane
authors.initials: J
authors.lastname: O
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Andrea
authors.initials: A
authors.lastname: Califano
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.affiliation: Gabriele Bartoli Brain Tumor Laboratory, Department of Neurosurgery, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (A.M.S., A.S.C., B.A., R.L., J.Y., C.S., R.R., J.O, P.C., J.N.B.); Department of Systems Biology, Columbia University, New York, New York (M.B., A.C.); Center for Computational Biology and Bioinformatics, Columbia University, New York, New York (M.B., A.C.); Department of Pathology and Cell Biology, Irving Research Cancer Center, Columbia University Medical Center, New York, New York (L.L.); High Throughput Screening Center, Columbia University Medical Center Judith P. Sulzberger Genome Center, New York, New York (R.R., H.L., C.K.); Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, New York (A.C.); Department of Biomedical Informatics, Columbia University, New York, New York (A.C.); Institute for Cancer Genetics, Columbia University, New York, New York (A.C.); Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York (A.C.).
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Bruce
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018481:Convection; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods; D005047:Etoposide / Q000008:administration & dosage*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D051379:Mice; D000075223:Poly-ADP-Ribose Binding Proteins; D016019:Survival Analysis; D059005:Topoisomerase II Inhibitors / Q000008:administration & dosage*
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618812:Top2a protein, mouse
keywords: convection-enhanced delivery; etoposide; glioma; proneural; topoisomerase