Oncotarget

Research Papers:

Simultaneous targeting of Eph receptors in glioblastoma

Sara Ferluga, Carla Maria Lema Tomé, Denise Mazess Herpai, Ralph D’Agostino and Waldemar Debinski _

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Oncotarget. 2016; 7:59860-59876. https://doi.org/10.18632/oncotarget.10978

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Abstract

Sara Ferluga1, Carla Maria Lema Tomé2, Denise Mazess Herpai1, Ralph D’Agostino3, Waldemar Debinski1

1Department 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

2Department of Neurobiology and Anatomy, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA

3Department of Biostatistical Sciences, Section on Biostatistics, Wake Forest University Health Sciences, Winston-Salem, NC, 27157, USA

Correspondence to:

Waldemar Debinski, email: debinski@wakehealth.edu

Keywords: Eph receptors, ephrin-A5, glioblastoma, cytotoxin, molecular targeting

Received: October 12, 2015     Accepted: July 16, 2016     Published: August 1, 2016

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.


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