title: Growth factor receptor expression varies among high-grade gliomas and normal brain: epidermal growth factor receptor has excellent properties for interstitial fusion protein therapy.
abstract: Convection-enhanced delivery of fusion proteins is a novel therapeutic approach for patients with relapsed or refractory high-grade gliomas. Multiple different fusion proteins have been produced that target different receptors on brain tumor cells. The sensitivity of different gliomas to fusion proteins has been shown to depend in part on the expression of the target receptor. We undertook a comparative study of the presence of the epidermal growth factor receptor (EGFR), interleukin-13 receptor (IL13R), interleukin-4 receptor (IL4R), and transferrin receptor (TfR) determined by immunofluorescence microscopy among fresh frozen tumor samples from 38 patients with high-grade gliomas (glioblastoma multiforme or anaplastic astrocytoma). The frequency of high receptor expression was 32 of 38 (84%) for EGFR, 30 of 38 (79%) for IL13R, 25 of 38 (66%) for TfR, and 17 of 38 (45%) for IL4R. Reactivity of normal brain endothelium was observed for TfR, and reactivity of normal brain astrocytes was observed for IL4R. Because of cross-reactivity of interleukin-13 with the IL4R-IL13Ralpha1 receptor, we infer reactivity of interleukin-13 with normal astrocytes. In contrast, EGFR was not observed in normal brain. A number of patients (10 of 38 patients) showed unequal expression of EGFR and IL13R. Thus, some patients may benefit more from interstitial therapy with an EGFR-directed fusion protein than from therapy with an IL13R-directed fusion protein and vice versa. The safety profile may be improved with an agent directed to EGFR versus agents directed to TfR, IL4R, or IL13R. Design of clinical trials of fusion proteins in patients with brain tumors may be enhanced by inclusion of relevant receptor density measurements.
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA.
authors.forename: Tie Fu
authors.initials: TF
authors.lastname: Liu
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Tatter
authors.forename: Mark C
authors.initials: MC
authors.lastname: Willingham
authors.forename: Mitchell
authors.initials: M
authors.lastname: Yang
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hu
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Frankel
mesh_terms: D001254:Astrocytoma / Q000378:metabolism; D014408:Biomarkers, Tumor; D001921:Brain / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000628:therapy; D066246:ErbB Receptors / Q000378:metabolism* / Q000627:therapeutic use*; D005909:Glioblastoma / Q000378:metabolism; D005910:Glioma / Q000378:metabolism* / Q000628:therapy; D006801:Humans; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin / Q000378:metabolism; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4 / Q000378:metabolism; D011990:Receptors, Transferrin / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C508181:IL13RA1 protein, human; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D019948:Receptors, Interleukin-4; D011990:Receptors, Transferrin; D011993:Recombinant Fusion Proteins; D066246:ErbB Receptors