RT Journal Article
SR Electronic
T1 Microarray Analysis Verifies Two Distinct Phenotypes of Glioblastomas Resistant to Antiangiogenic Therapy
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 2930
OP 2942
DO 10.1158/1078-0432.CCR-11-2390
VO 18
IS 10
A1 DeLay, Michael
A1 Jahangiri, Arman
A1 Carbonell, W. Shawn
A1 Hu, Yu-Long
A1 Tsao, Sean
A1 Tom, Maxwell Wing
A1 Paquette, Jesse
A1 Tokuyasu, Taku A.
A1 Aghi, Manish K.
YR 2012
UL http://clincancerres.aacrjournals.org/content/18/10/2930.abstract
AB Purpose: To identify mechanisms and mediators of resistance to antiangiogenic therapy in human glioblastoma. Experimental Design: We carried out microarray gene expression analysis and immunohistochemistry comparing 21 recurrent glioblastomas progressing during antiangiogenic treatment with VEGF neutralizing antibody bevacizumab to paired pretreatment tumors from the same patients. Results: Microarray analysis revealed that bevacizumab-resistant glioblastomas (BRG) had two clustering patterns defining subtypes that reflect radiographic growth patterns. Enhancing BRGs (EBRG) exhibited MRI enhancement, a long-established criterion for glioblastoma progression, and expressed mitogen-activated protein kinases, neural cell adhesion molecule-1 (NCAM-1), and aquaporin 4. Compared with their paired pretreatment tumors, EBRGs had unchanged vascularity and hypoxia, with increased proliferation. Nonenhancing BRGs (NBRG) exhibited minimal MRI enhancement but had FLAIR-bright expansion, a newer criterion for glioblastoma recurrence since the advent of antiangiogenic therapy, and expressed integrin α5, laminin, fibronectin1, and PDGFRβ. NBRGs had less vascularity, more hypoxia, and unchanged proliferation than their paired pretreatment tumors. Primary NBRG cells exhibited more stellate morphology with a 3-fold increased shape factor and were nearly 4-fold more invasive in Matrigel chambers than primary cells from EBRGs or bevacizumab-naive glioblastomas (P < 0.05). Conclusion: Using microarray analysis, we found two resistance patterns during antiangiogenic therapy with distinct molecular profiles and radiographic growth patterns. These studies provide valuable biologic insight into the resistance that has limited antiangiogenic therapy to date. Clin Cancer Res; 18(10); 2930–42. ©2012 AACR.