Immunohistochemical Analysis of Platelet-derived Growth Factor Receptor-α, -β, c-kit, c-abl, and Arg Proteins in Glioblastoma: Possible Implications for Patient Selection for Imatinib Mesylate Therapy
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Inhibition of tyrosine kinase (TK) receptors by synthetic small molecules has become a promising new therapy option in oncology. The TK inhibitor imatinib mesylate selectively targets PDGFR-α, -β, c-kit, c-abl and arg and has proven successful in the treatment of chronic myeloid leukaemia. In recurrent glioblastoma, phase II therapy trials using imatinib mesylate have been initiated. As only a fraction of patients seems to benefit from imatinib mesylate therapy and due to potential side effects and high costs of imatinib mesylate therapy, selection of the right patients is important. The goal of our study was to assess systematically immunohistochemical expression of the major TKs targeted by imatinib mesylate in glioblastoma, as expression of these factors could be used to select patients for imatinib mesylate therapy.
In a cohort of 101 glioblastoma patients, anti-PDGFR-α, -β, c-kit, c-abl and arg protein immunohistochemistry was performed. Expression of these proteins was assessed semi-quantitatively and correlated with patient survival.
PDGFR-α and arg expression in tumor cells was widespread in 1/101 cases, respectively. Focal PDGFR-α, -β, c-kit, c-abl and arg immunolabeling was detected in 25/101, 19/101, 4/101, 7/101 and 31/101 cases, respectively. Statistical analysis did not reveal any correlation between expression of the TKs and patient survival.
We show here for the first time in a large series of glioblastomas that PDGFR-α, -β, c-kit, c-abl and arg expression is immunohistochemically detectable in a fraction of cases. The value of anti-tyrosine kinase immunolabeling as predictive factor for patient selection remains to be clarified by comparative analysis of tumor tissue of therapy-responders versus non-responders.
Keywordsglioblastoma platelet-derived growth factor receptor-α -β c-kit c-abl and arg targeted therapy
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- 10.Raymond E, Brandes. A, Van Oosterom A, Dittrich C, Fumoleau P, Coudert C, Twelves C, De Balincourt C, Lacombe D, Van den Bent M: Multicentre phase II study of imatinib mesylate in patients with recurrent glioblastoma: An EORTC: NDDG/BTG Intergroup Study. J Clin Oncol 22: 1501, 2004 (abstract)Google Scholar
- 12.Hermanson, M, Funa, K, Hartman, M, Claesson-Welsh, L, Heldin, CH, Westermark, B, Nister, M 1992Platelet-derived growth factor and its receptors in human glioma tissue: expression of messenger RNA and protein suggests the presence of autocrine and paracrine loopsCancer Res5232133219PubMedGoogle Scholar
- 14.Kilic, T, Alberta, JA, Zdunek, PR, Acar, M, Iannarelli, P, O’Reilly, T, Buchdunger, E, Black, PM, Stiles, CD 2000Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine classCancer Res6051435150PubMedGoogle Scholar
- 15.Dowsett, M, Bartlett, J, Ellis, IO, Salter, J, Hills, M, Mallon, E, Watters, AD, Cooke, T, Paish, C, Wencyk, PM, Pinder, SE 2003Correlation between immunohistochemistry (HercepTest) and fluorescence in situ hybridization (FISH) for HER-2 in 426 breast carcinomas from 37 centresJ Pathol199418423CrossRefPubMedGoogle Scholar
- 16.Birner, P, Piribauer, M, Fischer, I, Gatterbauer, B, Marosi, C, Ambros, PF, Ambros, IM, Bredel, M, Oberhuber, G, Rossler, K, Budka, H, Harris, AL, Hainfellner, JA 2003Vascular patterns in glioblastoma influence clinical outcome and associate with variable expression of angiogenic proteins: evidence for distinct angiogenic subtypesBrain Pathol1313343PubMedGoogle Scholar
- 17.Hermanson, M, Funa, K, Koopmann, J, Maintz, D, Waha, A, Westermark, B, Heldin, CH, Wiestler, OD, Louis, DN, von-Deimling, A, Nister, M 1996Association of loss of heterozygosity on chromosome 17p with high platelet-derived growth factor alpha receptor expression in human malignant gliomasCancer Res56164171PubMedGoogle Scholar