Microarray Analysis Verifies Two Distinct Phenotypes of Glioblastomas Resistant to Antiangiogenic Therapy

• Published in: Clinical cancer research Vol. 18; no. 10; pp. 2930 - 2942
• Main Authors: DELAY, Michael, JAHANGIRI, Arman, SHAWN CARBONELL, W, HU, Yu-Long, TSAO, Sean, MAXWELL WING TOM, PAQUETTE, Jesse, TOKUYASU, Taku A, AGHI, Manish K
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.05.2012
• Subjects: Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic agents; Aquaporin 4 - biosynthesis; Aquaporin 4 - genetics; Bevacizumab; Biological and medical sciences; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; CD56 Antigen - biosynthesis; CD56 Antigen - genetics; Cell Hypoxia; Cell Proliferation; Cells, Cultured; Disease Progression; Drug Resistance, Neoplasm - genetics; Fibronectins - biosynthesis; Gene Expression Profiling; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Integrin alpha5 - biosynthesis; Laminin - biosynthesis; Medical sciences; Mitogen-Activated Protein Kinases - biosynthesis; Mitogen-Activated Protein Kinases - genetics; Neovascularization, Pathologic; Neurology; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Phenotype; Receptor, Platelet-Derived Growth Factor beta - biosynthesis; Tumor Microenvironment; Tumors of the nervous system. Phacomatoses; Vascular Endothelial Growth Factor A; Resistance; Malignant glioma; Nervous system diseases; Phenotype; Treatment; Analysis; Central nervous system disease; Glioblastoma; Malignant tumor; Antiangiogenic agent; Microarray; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-11-2390

To identify mechanisms and mediators of resistance to antiangiogenic therapy in human glioblastoma. 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. 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). 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.