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1.
Neuro Oncol ; 18(12): 1644-1655, 2016 12.
Article in English | MEDLINE | ID: mdl-27286795

ABSTRACT

BACKGROUND: Amplification of the epidermal growth factor receptor (EGFR) and its mutant EGFRvIII are among the most common genetic alterations in glioblastoma (GBM), the most frequent and most aggressive primary brain tumor. METHODS: In the present work, we analyzed the clonal evolution of these major EGFR aberrations in a small cohort of GBM patients using a unique surgical multisampling technique. Furthermore, we overexpressed both receptors separately and together in 2 patient-derived GBM stem cell lines (GSCs) to analyze their functions in vivo in orthotopic xenograft models. RESULTS: In human GBM biopsies, we identified EGFR amplification as an early event because EGFRvIII mutations emerge from intratumoral heterogeneity later in tumor development. To investigate the biological relevance of this distinct developmental pattern, we established experimental model systems. In these models, EGFR+ tumor cells showed activation of classical downstream signaling pathways upon EGF stimulation and displayed enhanced invasive growth without evidence of angiogenesis in vivo. In contrast, EGFRvIII+ tumors were driven by activation of the prototypical Src family kinase c-Src that promoted VEGF secretion leading to angiogenic tumor growth. CONCLUSIONS: The presented work shows that sequential EGFR amplification and EGFRvIII mutations might represent concerted evolutionary events that drive the aggressive nature of GBM by promoting invasion and angiogenesis via distinct signaling pathways. In particular, c-SRC may be an attractive therapeutic target for tumors harboring EGFRvIII as we identified this protein specifically mediating angiogenic tumor growth downstream of EGFRvIII.


Subject(s)
Brain Neoplasms/metabolism , ErbB Receptors/genetics , ErbB Receptors/metabolism , Glioblastoma/metabolism , Neovascularization, Pathologic/metabolism , Proto-Oncogene Proteins pp60(c-src)/metabolism , Brain/diagnostic imaging , Brain/pathology , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cell Line, Tumor , Evolution, Molecular , Glioblastoma/diagnostic imaging , Glioblastoma/genetics , Glioblastoma/pathology , Humans , Multimodal Imaging , Mutation , Neoplasm Invasiveness , Survival Analysis , Up-Regulation
2.
Cancer Res ; 74(13): 3567-78, 2014 Jul 01.
Article in English | MEDLINE | ID: mdl-24812275

ABSTRACT

As cancer treatment tools, oncolytic viruses (OV) have yet to realize what some see as their ultimate clinical potential. In this study, we have engineered a chimeric vesicular stomatitis virus (VSV) that is devoid of its natural neurotoxicity while retaining potent oncolytic activity. The envelope glycoprotein (G) of VSV was replaced with a variant glycoprotein of the lymphocytic choriomeningitis virus (LCMV-GP), creating a replicating therapeutic, rVSV(GP), that is benign in normal brain but can effectively eliminate brain cancer in multiple preclinical tumor models in vivo. Furthermore, it can be safely administered systemically to mice and displays greater potency against a spectrum of human cancer cell lines than current OV candidates. Remarkably, rVSV(GP) escapes humoral immunity, thus, for the first time, allowing repeated systemic OV application without loss of therapeutic efficacy. Taken together, rVSV(GP) offers a considerably improved OV platform that lacks several of the major drawbacks that have limited the clinical potential of this technology to date.


Subject(s)
Antigens, Viral/genetics , Glioblastoma/therapy , Glycoproteins/genetics , Membrane Glycoproteins/genetics , Oncolytic Virotherapy/adverse effects , Oncolytic Viruses/genetics , Vesicular stomatitis Indiana virus/genetics , Viral Envelope Proteins/genetics , Viral Proteins/genetics , Animals , Antibodies, Neoplasm/immunology , Antibodies, Viral/immunology , Cell Line, Tumor , Cricetinae , Female , Genetic Vectors , Humans , Immune Evasion , Immunity, Humoral , Lymphocytic choriomeningitis virus/genetics , Mice , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, SCID , Neoplasm Transplantation , Protein Engineering
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