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Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Oncology.
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2013 (English)In: Medical Oncology, ISSN 1357-0560, E-ISSN 1559-131X, Vol. 30, no 3, 638- p.Article in journal (Refereed) Published
Abstract [en]

The survival for patients with high-grade glioma is poor, and only a limited number of patients respond to the therapy. The aim of this study was to analyze the significance of using p38 MAPK phosphorylation as a prognostic marker in high-grade glioma patients and as a therapeutic target in combination chemotherapy with vandetanib. p38 MAPK phosphorylation was analyzed with immunohistochemistry in 90 high-grade glioma patients. Correlation between p38 MAPK phosphorylation and overall survival was analyzed with Mann-Whitney U test analysis. The effects on survival of glioblastoma cells of combining vandetanib with the p38 MAPK inhibitor SB 203580 were analyzed in vitro with the median-effect method with the fluorometric microculture cytotoxicity assay. Two patients had phosphorylated p38 MAPK in both the cytoplasm and nucleus, and these two presented with worse survival than patients with no detectable p38 MAPK phosphorylation or phosphorylated p38 MAPK only in the nucleus. This was true for both high-grade glioma patients (WHO grade III and IV, n = 90, difference in median survival: 6.1 months, 95 % CI [0.20, 23], p = 0.039) and for the subgroup with glioblastoma patients (WHO grade IV, n = 70, difference in median survival: 6.1 months, 95 % CI [0.066, 23], p = 0.043). The combination of vandetanib and the p38 MAPK inhibitor SB 203580 had synergistic effects on cell survival for glioblastoma-derived cells in vitro. In conclusion, p38 MAPK phosphorylation may be a prognostic marker for high-grade glioma patients, and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for glioma patients.

Place, publisher, year, edition, pages
2013. Vol. 30, no 3, 638- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-202678DOI: 10.1007/s12032-013-0638-0ISI: 000323662900047PubMedID: 23783486OAI: oai:DiVA.org:uu-202678DiVA: diva2:632758
Available from: 2013-06-25 Created: 2013-06-25 Last updated: 2017-12-06Bibliographically approved
In thesis
1. Prognostic Biomarkers and Target Proteins for Treatment of High-grade Gliomas
Open this publication in new window or tab >>Prognostic Biomarkers and Target Proteins for Treatment of High-grade Gliomas
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The survival for high-grade glioma patients is poor and the treatment may cause severe side effects. A common obstacle in the treatment is chemoresistance. To improve the quality of life and prolong survival for these patients prognostic biomarkers and new approaches for chemotherapy are needed. To this end, a strategy to evade chemoresistance was evaluated by combining chemotherapeutic drugs with agents inhibiting resistance mechanisms identified by a bioinformatic analysis (paper I). The prognostic value of 13 different proteins was analyzed in this thesis (papers II-IV). Two of them, p38 mitogen-activated protein kinase (MAPK) and protein tyrosine phosphatase non-receptor type 6 (PTPN6, also known as SHP1) were analyzed for their potential as targets in combination chemotherapy (in paper III and IV, respectively).

 

We found that:

  1. PTPN6 expression and methylation status may be important for survival of anaplastic glioma patients, p38 MAPK phosphorylation may be a potential negative prognostic biomarker for high-grade glioma patients and FGF2 expression may be a potential negative prognostic biomarker for proneural glioma patients.
  2. PTPN6 may be a useful target for combination chemotherapy with cisplatin, melphalan or bortezomib in high-grade gliomas. The following drug combinations; camptothecin combined with an EGFR or RAC1 inhibitor, imatinib combined with a Notch or RAC1 inhibitor, temozolomide combined with an EGFR or FAK inhibitor and vandetanib combined with a p38 MAPK inhibitor may be useful combination chemotherapy for high-grade gliomas.
Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 74 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 965
Keyword
High-grade glioma, prognostic biomarkers, combination chemotherapy, DNA methylation, FGF2, p38 MAPK, PTPN6, camptothecin, imatinib, vandetanib, EGFR, RAC1, Notch
National Category
Cell and Molecular Biology Cancer and Oncology
Research subject
Medical Science; Oncology
Identifiers
urn:nbn:se:uu:diva-215079 (URN)978-91-554-8839-0 (ISBN)
Public defence
2014-03-07, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjölds väg 20, Uppsala, 13:15 (English)
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Supervisors
Available from: 2014-02-13 Created: 2014-01-10 Last updated: 2014-04-29

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Sooman, LindaLennartsson, JohanGullbo, JoachimBergqvist, MichaelTsakonas, GeorgiosEdqvist, Per-HenrikPontén, FredrikAlafuzoff, IrinaPopova, SvetlanaBlomquist, Erik

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Sooman, LindaLennartsson, JohanGullbo, JoachimBergqvist, MichaelTsakonas, GeorgiosEdqvist, Per-HenrikPontén, FredrikAlafuzoff, IrinaPopova, SvetlanaBlomquist, Erik
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