title: Vandetanib combined with a p38 MAPK inhibitor synergistically reduces glioblastoma cell survival.
abstract: 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.
authors.affiliation: Section of Oncology, Department of Radiology, Oncology and Radiation Sciences, Rudbeck Laboratory, 751 85 Uppsala, Sweden. linda.sooman@onkologi.uu.se
authors.forename: Linda
authors.initials: L
authors.lastname: Sooman
authors.forename: Johan
authors.initials: J
authors.lastname: Lennartsson
authors.forename: Joachim
authors.initials: J
authors.lastname: Gullbo
authors.forename: Michael
authors.initials: M
authors.lastname: Bergqvist
authors.forename: Georgios
authors.initials: G
authors.lastname: Tsakonas
authors.forename: Fredrik
authors.initials: F
authors.lastname: Johansson
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Edqvist
authors.forename: Fredrik
authors.initials: F
authors.lastname: Pontén
authors.forename: Archita
authors.initials: A
authors.lastname: Jaiswal
authors.forename: Sanjay
authors.initials: S
authors.lastname: Navani
authors.forename: Irina
authors.initials: I
authors.lastname: Alafuzoff
authors.forename: Svetlana
authors.initials: S
authors.lastname: Popova
authors.forename: Erik
authors.initials: E
authors.lastname: Blomquist
authors.forename: Simon
authors.initials: S
authors.lastname: Ekman
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000627:therapeutic use*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D048051:p38 Mitogen-Activated Protein Kinases; C452423:vandetanib