对某些恶性脑部肿瘤而言，即使是很有前景的新药物也无法达到治疗效果。最近Heidelberg大学Wolf Müller等人发现了产生这种抵抗性的肿瘤标记物和分子机制。
该课题组发现某些脑部肿瘤(如星形细胞瘤)能使细胞表面的一种关键的蛋白质——“死亡受体(death receptor)”去活化。当药物与死亡受体接触后能引起细胞死亡。因此，一个完整的死亡受体可以作为某种治疗手段是否有效的肿瘤标记物。该研究发表在Clinical Cancer Research杂志上。
原发性脑部肿瘤来源于脑部细胞，尤其是恶性胶质母细胞瘤突变体。尽管对胶质母细胞瘤患者采取各种治疗手段，但患者一般在诊断出该肿瘤后两年内死亡。
研究人员对不同的脑部肿瘤(如星形细胞瘤)进行研究，发现当死亡受体DR4的基因发生“启动子甲基化”时，超过75%的该基因都会关闭。这说明基因片段中甲基化群的积累对该基因的表达很重要。
死亡受体DR4对开发受体特异性疗法(receptor-specific therapy)是一个值得引起人注意的靶标。目前已有已开发出来一种名为Mapatumumab的抗体蛋白，能够直接与死亡受体结合并引发细胞死亡。该药物目前正在进行临床阶段的测试来治疗肺癌。（生物谷Bioon.com）
生物谷推荐原始出处：
Clinical Cancer Research 15, 5457, September 1, 2009. doi: 10.1158/1078-0432.CCR-09-1125
Epigenetic Silencing of Death Receptor 4 Mediates Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Resistance in Gliomas
Agnes Elias1, Markus D. Siegelin1, Albert Steinmüller1, Andreas von Deimling1,2, Ulrike Lass2, Bernhard Korn3 and Wolf Mueller1
Authors' Affiliations: 1 Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-Universit?t Heidelberg; 2 Clinical Cooperation Unit Neuropathology G380 and 3 Genomics and Proteomics Core Facility, German Cancer Research Center, Heidelberg, Germany
Purpose: To identify and characterize epigenetically regulated genes able to predict sensitivity or resistance to currently tested chemotherapeutic agents in glioma therapy.
Experimental Design: We used methylation-sensitive BeadArray technology to identify novel epigenetically regulated genes associated with apoptosis and with potential therapeutic targets in glioma therapy. To elucidate the functional consequences of promoter methylation in the identified target death receptor 4 (DR4), we investigated tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–mediated and anti-DR4–mediated apoptosis in glioma cell lines (U373 and A172) with loss of DR4 and one glioma cell line (LN18) with robust DR4 expression.
Results: In human astrocytic tumors, we detected DR4 promoter hypermethylation in 60% (n = 5) of diffuse astrocytomas WHO grade 2, in 75% (n = 8) of anaplastic astrocytomas WHO grade 3, and in 70% of glioblastomas WHO grade 4 (n = 33). DR4 is a cell surface protein restricted to glioma cells and is targeted by TRAIL. Glioma cell lines U373 and A172 harbored heavily methylated DR4 promoters, and 5-aza-2-deoxycytidine–mediated demethylation reconstituted DR4 expression in these cell lines. Functional knockdown of DR4 by DR4-specific small interfering RNA in TRAIL-sensitive glioma cell line LN18 significantly mitigated apoptosis induced by an agonistic anti-DR4 antibody. 5-Aza-2-deoxycytidine–mediated demethylation resulted in a functional reconstitution of DR4 on the cell surface of TRAIL-resistant glioma cell line U373 and sensitized U373 to TRAIL-mediated apoptosis. Suppression of DR4 by small interfering RNA in demethylated U373 successfully reestablished the TRAIL-resistant phenotype of U373.
Conclusions: DR4 promoter methylation is frequent in human astrocytic gliomas, and epigenetic silencing of DR4 mediates resistance to TRAIL/DR4-based glioma therapies.
