title: Simultaneous targeting of Eph receptors in glioblastoma.
abstract: Eph tyrosine kinase receptors are frequently overexpressed and functional in many cancers, and they are attractive candidates for targeted therapy. Here, we analyzed the expression of Eph receptor A3, one of the most up-regulated factors in glioblastoma cells cultured under tumorsphere-forming conditions, together with EphA2 and EphB2 receptors. EphA3 was overexpressed in up to 60% of glioblastoma tumors tested, but not in normal brain. EphA3 was localized in scattered areas of the tumor, the invasive ring, and niches near tumor vessels. EphA3 co-localized with macrophage/leukocyte markers, suggesting EphA3 expression on tumor-infiltrating cells of bone marrow origin. We took advantage of the fact that ephrinA5 (eA5) is a ligand that binds EphA3, EphA2 and EphB2 receptors, and used it to construct a novel targeted anti-glioblastoma cytotoxin. The eA5-based cytotoxin potently and specifically killed glioblastoma cells with an IC50 of at least 10-11 M. This and similar cytotoxins will simultaneously target different compartments of glioblastoma tumors while mitigating tumor heterogeneity.
authors: Department of Cancer Biology, Radiation Oncology and Neurosurgery, Brain Tumor Center of Excellence, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors: Sara
authors: S
authors: Ferluga
authors: Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors: Carla Maria Lema
authors: CM
authors: Tomé
authors: Department of Cancer Biology, Radiation Oncology and Neurosurgery, Brain Tumor Center of Excellence, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors: Denise Mazess
authors: DM
authors: Herpai
authors: Department of Biostatistical Sciences, Section on Biostatistics, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA.
authors: Ralph
authors: R
authors: D'Agostino
authors: Department of Cancer Biology, Radiation Oncology and Neurosurgery, Brain Tumor Center of Excellence, Comprehensive Cancer Center of Wake Forest Baptist Medical Center, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors: Waldemar
authors: W
authors: Debinski
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000276:immunology / Q000628:therapy*; D036386:Ephrin-A5 / Q000276:immunology / Q000378:metabolism*; D005909:Glioblastoma / Q000276:immunology / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000922:Immunotoxins / Q000235:genetics / Q000627:therapeutic use*; D011485:Protein Binding; D020794:Receptor Protein-Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D036121:Receptor, EphA3; D057127:Single-Chain Antibodies / Q000235:genetics; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D036386:Ephrin-A5; D000922:Immunotoxins; D057127:Single-Chain Antibodies; C491718:EPHA3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D036121:Receptor, EphA3
keywords: Eph receptors; cytotoxin; ephrin-A5; glioblastoma; molecular targeting