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Expression of Interleukin-13 Receptor A2 in Glioblastoma Multiforme: Implications for Targeted Therapies

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Expression of Interleukin-13 Receptor A2 in Glioblastoma Multiforme: Implications for Targeted Therapies Priority Report Expression of Interleukin-13 Receptor A2 in Glioblastoma Multiforme: Implications for Targeted Therapies John S. Jarboe,1 Kory R. Johnson,2 Yong Choi,1 Russell R. Lonser,3 and John K. Park1 1Surgical and Molecular Neuro-oncology Unit, 2Bioinformatics Group, Intramural Information Technology Program, Division of Intramural Research, and 3Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland Abstract quantities of IL4, an effect referred to as IL4-independent IL13 Glioblastoma multiforme is the most common primary binding (2–5). The cell surface expression of a monomeric 42-kDa malignant brain tumor and despite treatment with surgery, receptor capable of binding IL13 but not IL4, termed IL13 receptor a2 (IL13Ra2), was used to explain this effect (6). It was also initially radiation, and chemotherapy, the median survival of patients a with glioblastoma multiforme is f1 year. Glioblastoma multi- reported that significant IL13R 2 expression, as assessed by Northern blotting, occurs exclusively in the testes and in malignant forme explants and cell lines have been reported to over- a express the interleukin-13 receptor A2 subunit (IL13RA2) glioma tissues (7). The putative relative restriction of IL13R 2 relative to nonneoplastic brain. Based on this finding, a expression to glioma cells was subsequently used as a rationale for recombinant cytotoxin composed of IL13 ligand and a trun- the development of several IL13-based treatment strategies including a recombinant cytotoxin composed of IL13 and a cated form of Pseudomonas aeruginosa exotoxin A (IL13- PE38QQR) was developed for the targeted treatment of truncated form of Pseudomonas aeruginosa exotoxin A (IL13- glioblastoma multiforme tumors. In a recently completed PE38QQR; ref. 8). IL13-PE38QQR internalized by cells expressing phase III clinical trial, however, IL13-PE38QQR was found to IL13 receptor complexes enzymatically inhibits protein synthesis be no more effective than an existing therapy in prolonging and causes apoptotic cell death (9). The IC50 of IL13-PE38QQR survival. To determine possible explanations for this result, in IL13 receptor–expressing cells has been reported to be as low as we analyzed the relative expression levels of IL13RA2in 0.1 ng/mL (8). A phase III clinical trial assessing the efficacy of IL13- glioblastoma multiforme and nonneoplastic brain specimens PE38QQR administered intratumorally via convection-enhanced using publicly available oligonucleotide microarray data- delivery has been completed recently, but detailed results have not bases, quantitative real-time reverse transcription PCR, and as yet been published. NeoPharm, the study sponsor, has however released preliminary information indicating that the median immunohistochemical staining. Increased expression of the IL13Ra2 gene relative to nonneoplastic brain was observed survival of patients treated with IL13-PE38QQR was 36.4 weeks, in 36 of 81 (44%) and 8 of 17 (47%) tumor specimens by whereas that of patients treated with a slow-release carmustine microarray and quantitative real-time reverse transcription wafer was 35.3 weeks (10). To identify factors that may have influenced the outcomes of IL13-PE38QQR–treated patients, we PCR analyses, respectively. Immunohistochemical staining of a tumor specimens showed highly variable expression of analyzed the relative expression levels of IL13R 2 in glioblastoma IL13RA2 protein both within and across specimens. These multiforme and nonneoplastic brain specimens. Using two data indicate that prescreening of subjects may be of benefit independent methods and two independent sets of patient speci- A mens, we determined that the percentage of glioblastoma multi- in future trials of IL13R 2 targeting therapies. [Cancer Res a 2007;67(17):7983–6] forme tumors with relative overexpression of IL13R 2 is <50%. The relevance of our findings on the analysis of completed, as well as the design of future, IL13Ra2 targeting clinical trials is discussed. Introduction A highly sought after treatment for glioblastoma multiforme is one that eradicates neoplastic cells while sparing normal brain Materials and Methods tissues. A cell surface antigen differentially overexpressed by Microarray analysis. The Oncomine Web site4 (11) was used to examine glioblastoma multiforme cells could serve as a therapeutic target the differential expression of IL13Ra2 in brain tissues. The microarray data and the basis for such a treatment. Interleukin 4 (IL4) and of Sun et al. (12) was identified as an appropriate data set for the detailed interleukin 13 (IL13) are two immune regulatory cytokines that can comparison of IL13Ra2 gene expression in glioblastoma multiforme and nonneoplastic brain specimens and could be downloaded from the National compete for binding to a heterodimeric cell surface receptor 5 consisting of a 140-kDa IL4 receptor h subunit and a 45-kDa IL13 Center for Biotechnology Information Gene Expression Omnibus as record GDS1962. All statistical analyses were done using the program R-2.4.1.6 receptor a1 subunit (1). In contrast to most normal body tissues, Examination of the data by covariance-based principal component analysis high-grade gliomas can also bind IL13 in the presence of excess and Pearson’s correlation analysis was used to confirm the suitability of this data set for investigation of IL13Ra2 gene expression. The differential expression of IL13Ra2 between glioblastoma multiforme and nonneoplastic brain specimens was examined by Tukey box plot, XY scatterplot, and Note: Supplementary data for this article are available at Cancer Research Online density plot. (http://cancerres.aacrjournals.org/). Requests for reprints: John K. Park, Surgical and Molecular Neuro-oncology Unit, National Institute of Neurological Disorders and Stroke, NIH, Room 2B-1002, 35 Convent Drive, MSC 3706, Bethesda, MD 20892. Phone: 301-402-6935; Fax: 301-480- 0099; E-mail: [email protected]. 4 http://www.oncomine.org I2007 American Association for Cancer Research. 5 http://www.ncbi.nlm.nih.gov/geo doi:10.1158/0008-5472.CAN-07-1493 6 http://www.r-project.org www.aacrjournals.org 7983 Cancer Res 2007; 67: (17). September 1, 2007 Downloaded from cancerres.aacrjournals.org on October 3, 2021. © 2007 American Association for Cancer Research. Cancer Research Quantitative real-time reverse transcription PCR. Seventeen glio- plot was generated and confirmed that the distribution of expres- blastoma multiforme and six nonneoplastic brain tissue samples, obtained sion of IL13Ra2 among glioblastoma multiforme samples and via neurosurgical resection in accordance with the NIH (NIH, Bethesda, nonneoplastic brain samples is overlapping and mixed (Fig. 1C). MD) institutional review board–approved human tissue collection proto- Quantitative real-time reverse transcription PCR. To confirm cols, were randomly selected for study. Informed consent for tissue the oligonucleotide microarray finding that less than half of collection was obtained from each subject. Total RNA was extracted from a snap-frozen tissues using Trizol reagent (Invitrogen). The RNA was treated glioblastoma multiforme samples have overexpression of IL13R 2, with DNase I (Invitrogen) to eliminate traces of genomic DNA and cDNAs we used both a different set of patient samples and a different were synthesized using SuperScript II Reverse Transcriptase (Invitrogen) method, quantitative real-time reverse transcription PCR (QRT- and random primers (Invitrogen). All procedures were done according to PCR). QRT-PCR analyses of 17 glioblastoma multiforme and 6 the manufacturer’s protocols. The integrity of the cDNA template was nonneoplastic brain samples were done (Fig. 2). The mean IL13Ra2 verified by standard PCR amplification of the human 18S rRNA product at expression level of the six nonneoplastic brain specimens was an annealing temperature of 50jC for 15 cycles. The primer sequences for assigned an arbitrary value of 1.0 and the fold increase in expres- ¶ ¶ the 18S rRNA product were 5 -GGAATAATGGAATAGGACC-3 (sense) and sion for each of the glioblastoma multiforme specimens relative to ¶ ¶ 5 -GCTCCACCAACTAAGAAC-3 (antisense). Quantitative PCR was carried this mean was determined. Individual glioblastoma multiforme out using FastStart SYBR Green Master (Roche) in the Prism 7900HT samples were considered to have significantly different expression sequence detection system (Applied Biosystems) for 40 cycles. The primers a for amplification of IL13Ra2were5¶-AATGGCTTTCGTTTGCTTGG-3¶ of IL13R 2 compared with nonneoplastic brain samples when the (sense) and 5¶-ACGCAATCCATATCCTGAAC-3¶ (antisense; 13). A cycle threshold value in the linear range of amplification was selected for each sample and normalized for level of 18S rRNA expression. The relative IL13Ra2 expression level of each sample was calculated using the formula DDCT 2 , where DDCT is the difference between the selected cycle threshold value of a particular sample and the mean of the cycle thresholds of the nonneoplastic brain samples (14). The mean IL13Ra2 expression level of the six nonneoplastic brain samples was assigned an expression value of 1.0 and the fold increase or decrease in IL13Ra2 expression was determined for each control and glioblastoma multiforme sample. Individual glioblastoma multiforme samples were considered to have significantly different expression of IL13Ra2 compared with nonneoplastic brain when the P value for a t test comparing the two was <0.05. Experiments were done in triplicate.
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