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Interleukin-13 Receptor 2, EphA2, and Fos-Related Antigen 1 as Molecular Denominators of High-Grade Astrocytomas and Specific Targets for Combinatorial Therapy

Authors' Affiliations: Brain Tumor Center of Excellence, Comprehensive Cancer Center, Departments of ¹ Neurosurgery, ² Radiation Oncology, ³ Cancer Biology, and ⁴ Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina

Requests for reprints: Waldemar Debinski, Brain Tumor Center of Excellence, Comprehensive Cancer Center of Wake Forest University, Departments of Neurosurgery, Radiation Oncology, and Cancer Biology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. Phone: 336-716-9712; Fax: 336-713-7639; E-mail: debinski{at}wfubmc.edu.

Purpose: We investigated the expression of interleukin-13 receptor 2 (IL-13R2), EphA2, and Fos-related antigen 1 (Fra-1) in astrocytomas and normal brain. We sought to document whether the expression of the three factors changed with progression to higher grade malignancy and whether two or three targets in combination might be sufficient to target all patients with high-grade astrocytomas.

Experimental Design: Immunohistochemistry was done for IL-13R2, EphA2, and Fra-1 using human brain tumor tissue microarrays containing 30 specimens of WHO grades II and III astrocytomas, 46 glioblastoma multiformes (GBM), and 9 normal brain samples. Sections were scored based on frequency and intensity of expression. Western blotting was done for all three markers using GBM tumor specimens and xenograft cell lines. Two cytotoxins, IL-13.E13K.PE38QQR and ephrinA1-PE38QQR, which target IL-13R2 or EphA2, respectively, were tested for cytotoxicity against human GBM primary explant cells and established cells.

Results: Expression of all three proteins was significantly higher in GBM compared with normal brain, low-grade, and anaplastic astrocytomas. Greater than 95% of GBM overexpressed at least two of the three markers. Importantly, every GBM overexpressed at least one marker. Human GBM primary explant cells and cell lines were potently killed by IL-13.E13K.PE38QQR and ephrinA1-PE38QQR, in accordance with their level of expression of IL-13R2 and EphA2, respectively.

Conclusions: IL-13R2, EphA2, and Fra-1 are attractive therapeutic targets representing molecular denominators of high-grade astrocytomas. One hundred percent of GBM tumors overexpress at least one of these proteins, providing the basis for rational combinatorial targeted therapies/diagnostics suitable for all patients with this disease.