title: Modulating antiangiogenic resistance by inhibiting the signal transducer and activator of transcription 3 pathway in glioblastoma.
abstract: Determining the mechanism of treatment failure of VEGF signaling inhibitors for malignant glioma patients would provide insight into approaches to overcome therapeutic resistance. In this study, we demonstrate that human glioblastoma tumors failing bevacizumab have an increase in the mean percentage of p-STAT3-expressing cells compared to samples taken from patients failing non-antiangiogenic therapy containing regimens. Likewise, in murine xenograft models of glioblastoma, the mean percentage of p-STAT3-expressing cells in the gliomas resistant to antiangiogenic therapy was markedly elevated relative to controls. Administration of the JAK/STAT3 inhibitor AZD1480 alone and in combination with cediranib reduced tumor hypoxia and the infiltration of VEGF inhibitor-induced p-STAT3 macrophages. Thus, the combination of AZD1480 with cediranib markedly reduced tumor volume, and microvascular density, indicating that up regulation of the STAT3 pathway can mediate resistance to antiangiogenic therapy and combinational approaches may delay or overcome resistance.
authors.affiliation: Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. jdegroot@mdanderson.org
authors.forename: John
authors.initials: J
authors.lastname: de Groot
authors.forename: Ji
authors.initials: J
authors.lastname: Liang
authors.forename: Ling-Yuan
authors.initials: LY
authors.lastname: Kong
authors.forename: Jun
authors.initials: J
authors.lastname: Wei
authors.forename: Yuji
authors.initials: Y
authors.lastname: Piao
authors.forename: Gregory
authors.initials: G
authors.lastname: Fuller
authors.forename: Wei
authors.initials: W
authors.lastname: Qiao
authors.forename: Amy B
authors.initials: AB
authors.lastname: Heimberger
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D005909:Glioblastoma / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000096:biosynthesis; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D064231:Nestin; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D007211:Indoles
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D011720:Pyrazoles; D011743:Pyrimidines; D011799:Quinazolines; D050796:STAT3 Transcription Factor; C545606:AZD 1480; C577484:NES protein, human; C577485:Nes protein, mouse; C500926:cediranib; D007211:Indoles