Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma

Tadahiko Kubo, Sajida Piperdi, Jeremy Rosenblum, Cristina R. Antonescu, Wen Chen, Han Soo Kim, Andrew G. Huvos, Rebecca Sowers, Paul A. Meyers, John H. Healey, Richard Gorlick

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Abstract

The purpose of this review was to determine whether imatinib mesylate (STI571, Gleevec) has a role in the treatment of osteosarcoma. The expression of platelet-derived growth factor (PDGF) receptor and its ligand was examined in a panel of surgical specimens obtained from 54 osteosarcoma patients, and then the expression was compared with prognosis. The effects of imatinib mesylate on growth and molecular events in 10 patient-derived osteosarcoma cell cultures yvere investigated. Immunohistochemical studies demonstrated frequent expression of PDGF-AA (80.4%) and PDGF-α receptor (79.6%) and their correlation yyith inferior event-free survival (P < .05). PDGF-B-B and PDGF-β-receptor expressions were also frequent (75.4% and 86%, respectively); however, statistically significant inferior event-free survival was not demonstrated (P = .15). In vitro studies demonstrated that imatinib mesylate had a variable cytotoxic effect on various osteosarcoma primary cultures, with an IC30 of 5.6 μM to 9.5 μM, and blocked the PDGF-induced intracellular signal transduction as well as inhibition of downstream Akt phosphorylation. Mitogen-activated protein kinase (MAPK) was constitutively activated despite PDGF stimulation and imatinib mesylate treatment in 7 of 10 osteosarcoma cultures, perhaps explaining uncontrolled proliferation and relative unresponsiveness to imatinib. Imatinib mesylate could not be viewed as having a role as a single agent at current conventional doses for the treatment of osteosarcoma. These findings predicted activity in osteosarcoma clinical trials and suggested that in vitro model systems predict clinical behavior and that PDGF and its receptor expression could potentially be used for determining prognosis of osteosarcoma.

Original languageEnglish (US)
Pages (from-to)2119-2129
Number of pages11
JournalCancer
Volume112
Issue number10
DOIs
StatePublished - May 15 2008

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Platelet-Derived Growth Factor Receptors
Osteosarcoma
Platelet-Derived Growth Factor
Therapeutics
Disease-Free Survival
Proto-Oncogene Proteins c-sis
Imatinib Mesylate
Mitogen-Activated Protein Kinases
Signal Transduction
Cell Culture Techniques
Phosphorylation
Clinical Trials
Ligands

Keywords

  • Gleevec
  • Imatinib mesylate
  • Osteosarcoma
  • Platelet-derived growth factor receptor (PDGF)
  • Prognosis
  • STI-571

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Kubo, T., Piperdi, S., Rosenblum, J., Antonescu, C. R., Chen, W., Kim, H. S., ... Gorlick, R. (2008). Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma. Cancer, 112(10), 2119-2129. https://doi.org/10.1002/cncr.23437

Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma. / Kubo, Tadahiko; Piperdi, Sajida; Rosenblum, Jeremy; Antonescu, Cristina R.; Chen, Wen; Kim, Han Soo; Huvos, Andrew G.; Sowers, Rebecca; Meyers, Paul A.; Healey, John H.; Gorlick, Richard.

In: Cancer, Vol. 112, No. 10, 15.05.2008, p. 2119-2129.

Research output: Contribution to journalArticle

Kubo, T, Piperdi, S, Rosenblum, J, Antonescu, CR, Chen, W, Kim, HS, Huvos, AG, Sowers, R, Meyers, PA, Healey, JH & Gorlick, R 2008, 'Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma', Cancer, vol. 112, no. 10, pp. 2119-2129. https://doi.org/10.1002/cncr.23437
Kubo, Tadahiko ; Piperdi, Sajida ; Rosenblum, Jeremy ; Antonescu, Cristina R. ; Chen, Wen ; Kim, Han Soo ; Huvos, Andrew G. ; Sowers, Rebecca ; Meyers, Paul A. ; Healey, John H. ; Gorlick, Richard. / Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma. In: Cancer. 2008 ; Vol. 112, No. 10. pp. 2119-2129.
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AU - Huvos, Andrew G.

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