title: Combined PDGFR and HDAC Inhibition Overcomes PTEN Disruption in Chordoma.
abstract: BACKGROUND
  The majority of chordomas show activation of the platelet-derived growth factor receptor (PDGFR). Based on in vitro intertumoral variation in response to recombinant PDGF protein and PDGFR inhibition, and variable tumor response to imatinib, we hypothesized that chordomas resistant to PDGFR inhibition may possess downstream activation of the pathway.
  
  
  METHODS
  Molecular profiling was performed on 23 consecutive chordoma primary tissue specimens. Primary cultures established from 20 of the 23 specimens, and chordoma cell lines, UCH-1 and UCH-2, were used for in vitro experiments.
  
  
  RESULTS
  Loss of heterozygosity (LOH) at the phosphatase and tensin homolog (PTEN) locus was observed in 6 specimens (26%). PTEN disruption statistically correlated with increased Ki-67 proliferation index, an established marker of poor outcome for chordoma. Compared to wild type, PTEN deficient chordomas displayed increased proliferative rate, and responded less favorably to PDGFR inhibition. PTEN gene restoration abrogated this growth advantage. Chordomas are characterized by intratumoral hypoxia and local invasion, and histone deacetylase (HDAC) inhibitors are capable of attenuating both hypoxic signaling and cell migration. The combination of PDGFR and HDAC inhibition effectively disrupted growth and invasion of PTEN deficient chordoma cells.
  
  
  CONCLUSIONS
  Loss of heterozygosity of the PTEN gene seen in a subset of chordomas is associated with aggressive in vitro behavior and strongly correlates with increased Ki-67 proliferative index. Combined inhibition of PDGFR and HDAC attenuates proliferation and invasion in chordoma cells deficient for PTEN.
authors.affiliation: Department of Neurological Surgery, University of Virginia, PO BOX 800212, Charlottesville, VA 22908, United States of America.
authors.forename: Dae-Hee
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Department of Microbiology, University of Virginia, PO BOX 800734, Charlottesville, VA 22908, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, United States of America.
authors.forename: Amin B
authors.initials: AB
authors.lastname: Kassam
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, United States of America.
authors.forename: Myung-Jin
authors.initials: MJ
authors.lastname: Park
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, United States of America.
authors.forename: Paul
authors.initials: P
authors.lastname: Gardner
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Prevedello
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, United States of America.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Henry
authors.affiliation: Department of Pathology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, United States of America.
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh, 5150 Centre Avenue, Pittsburgh, PA 15232, United States of America.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Beumer
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh, 5150 Centre Avenue, Pittsburgh, PA 15232, United States of America.
authors.forename: Hussein
authors.initials: H
authors.lastname: Tawbi
authors.affiliation: Department of Neurological Surgery, University of Virginia, PO BOX 800212, Charlottesville, VA 22908, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Williams
authors.affiliation: Department of Neurological Surgery, University of Virginia, PO BOX 800212, Charlottesville, VA 22908, United States of America.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Shaffrey
authors.affiliation: University of Pittsburgh Cancer Institute, University of Pittsburgh, 5150 Centre Avenue, Pittsburgh, PA 15232, United States of America.
authors.forename: Merrill J
authors.initials: MJ
authors.lastname: Egorin
authors.affiliation: Department of Microbiology, University of Virginia, PO BOX 800734, Charlottesville, VA 22908, United States of America.
authors.forename: Roger
authors.initials: R
authors.lastname: Abounader
authors.affiliation: Department of Neurological Surgery, University of Virginia, PO BOX 800212, Charlottesville, VA 22908, United States of America; Neuro-Oncology Branch, National Cancer Institute, NIH, 9030 Old Georgetown Rd, B82/Rm225, Bethesda, MD 20892, United States of America.
authors.forename: Deric M
authors.initials: DM
authors.lastname: Park
mesh_terms: D000328:Adult; D000368:Aged; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D002817:Chordoma / Q000378:metabolism / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity / Q000187:drug effects*; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D055815:Young Adult
chemical_list: D056572:Histone Deacetylase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D017479:Receptors, Platelet-Derived Growth Factor; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human