Expression of interleukin-13 receptor α2 in glioblastoma multiforme:: Implications for targeted therapies
Expression of interleukin-13 receptor α2 in glioblastoma multiforme:: Implications for targeted therapies
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DOI：
10.1158/0008-5472.can-07-1493
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发表时间：
2007-09-01
期刊：
影响因子：
11.2
通讯作者：
Park, John K.
中科院分区：
文献类型：
--
作者：
Jarboe, John S.;Johnson, Kory R.;Park, John K.
多形性胶质母细胞瘤是最常见的原发性恶性脑肿瘤，尽管采用手术、放疗和化疗治疗，但多形性胶质母细胞瘤患者的中位生存期与1年相似。据报道，多形性胶质母细胞瘤外植体和细胞系相对于非肿瘤性脑过度表达白细胞介素-13受体α 2亚基（ILI 3R α 2）。基于这一发现，开发了由IL 13配体和截短形式的铜绿假单胞菌外毒素A（IL-PE 38 QQR）组成的重组细胞毒素，用于多形性胶质母细胞瘤肿瘤的靶向治疗。然而，在最近完成的III期临床试验中，发现IL 13-PE 38 QQR在延长生存期方面并不比现有疗法更有效。为了确定这一结果的可能解释，我们使用公开的寡核苷酸微阵列数据库、定量实时逆转录PCR和免疫组织化学染色分析了多形性胶质母细胞瘤和非肿瘤性脑标本中IL 13 R α 2的相对表达水平。通过微阵列和定量实时逆转录PCR分析，分别在81例肿瘤标本中的36例（44%）和17例肿瘤标本中的8例（47%）中观察到IL 13 R α 2基因相对于非肿瘤性脑组织的表达增加。肿瘤标本的免疫组织化学染色显示IL 13 R α 2蛋白在标本内和标本间的表达高度可变。这些数据表明，受试者的预筛选可能在IL 13 R α 2靶向治疗的未来试验中受益。
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 similar to I year. Glioblastoma multiforme explants and cell lines have been reported to overexpress the interleukin-13 receptor alpha 2 subunit (ILI3R alpha 2) relative to nonneoplastic brain. Based on this finding, a recombinant cytotoxin composed of IL13 ligand and a truncated form of Pseudomonas aeraginosa exotoxin A (IL-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 IL13R alpha 2 in glioblastoma multiforme and nonneoplastic brain specimens using publicly available oligonucleotide microarray databases, quantitative real-time reverse transcription PCR, and inummohistochemical staining. Increased expression of the IL13R alpha 2 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. Inummohistochemical staining of tumor specimens showed highly variable expression of IL13R alpha 2 protein both within and across specimens. These data indicate that prescreening of subjects may he of benefit in future trials of IL13R alpha 2 targeting therapies.