Expression of interleukin-13 receptor alpha2 in glioblastoma multiforme: implications for targeted therapies.
Glioblastoma multiforme is the most common primary malignant brain tumor and despite treatment with surgery, radiation, and chemotherapy, the median survival of patients with glioblastoma multiforme is approximately 1 year. Glioblastoma multiforme explants and cell lines have been reported to overexpress the interleukin-13 receptor alpha2 subunit (IL13Ralpha2) relative to nonneoplastic brain. Based on this finding, a recombinant cytotoxin composed of IL13 ligand and a truncated form of Pseudomonas aeruginosa exotoxin A (IL13-PE38QQR) was developed for the targeted treatment of glioblastoma multiforme tumors. In a recently completed phase III clinical trial, however, IL13-PE38QQR was found to be no more effective than an existing therapy in prolonging survival. To determine possible explanations for this result, we analyzed the relative expression levels of IL13Ralpha2 in glioblastoma multiforme and nonneoplastic brain specimens using publicly available oligonucleotide microarray databases, quantitative real-time reverse transcription PCR, and immunohistochemical staining. Increased expression of the IL13Ralpha2 gene relative to nonneoplastic brain was observed in 36 of 81 (44%) and 8 of 17 (47%) tumor specimens by microarray and quantitative real-time reverse transcription PCR analyses, respectively. Immunohistochemical staining of tumor specimens showed highly variable expression of IL13Ralpha2 protein both within and across specimens. These data indicate that prescreening of subjects may be of benefit in future trials of IL13Ralpha2 targeting therapies.
Jarboe
John S
JS
Surgical and Molecular Neuro-Oncology Unit, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, MD 20892, USA.
Johnson
Kory R
KR
Choi
Yong
Y
Lonser
Russell R
RR
Park
John K
JK
D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018390:Gene Targeting; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007150:Immunohistochemistry; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection