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Combined PDGFR and HDAC inhibition overcomes PTEN disruption in Chordoma

Lee, DH and Zhang, Y and Kassam, AB and Park, MJ and Gardner, P and Prevedello, D and Henry, S and Horbinski, C and Beumer, JH and Tawbi, H and Williams, BJ and Shaffrey, ME and Egorin, MJ and Abounader, R and Park, DM (2015) Combined PDGFR and HDAC inhibition overcomes PTEN disruption in Chordoma. PLoS ONE, 10 (8).

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Abstract

© 2015 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Lee, DH
Zhang, Y
Kassam, AB
Park, MJ
Gardner, Ppagst28@pitt.eduPAGST28
Prevedello, D
Henry, S
Horbinski, C
Beumer, JHjhb11@pitt.eduJHB11
Tawbi, Hhat9@pitt.eduHAT9
Williams, BJ
Shaffrey, ME
Egorin, MJ
Abounader, R
Park, DM
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorLoeb, David M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Centers: Other Centers, Institutes, or Units > Pittsburgh Cancer Institute
Date: 6 August 2015
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: PLoS ONE
Volume: 10
Number: 8
DOI or Unique Handle: 10.1371/journal.pone.0134426
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Neurological Surgery
School of Medicine > Pathology
Refereed: Yes
Date Deposited: 23 Aug 2016 14:27
Last Modified: 13 Oct 2017 23:00
URI: http://d-scholarship.pitt.edu/id/eprint/28406

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