2016年7月11日讯 /生物谷BIOON/ --近日，来自美国西北大学的研究人员在国际学术期刊Molecular Cancer Research上发表了一篇文章，他们通过研究找到了治疗多形性成胶质细胞瘤及神经胶质瘤干细胞的潜在靶点。多形性成胶质细胞瘤目前仍然是最致命的恶性脑瘤，而神经胶质瘤干细胞会促进治疗抵抗和肿瘤复发。
在这项最新研究中，研究人员发现MAPK作用激酶（MNK）是治疗多形性成胶质细胞瘤中神经胶质瘤干细胞群体的潜在靶点。研究分析表明相比于其他疾病亚型来说，间叶细胞样多形性成胶质细胞瘤的两个MNK基因（MKNK1和MKNK2）均发生表达上调。
MKNK1的表达与神经胶质瘤级别增加有关，还与间叶细胞样神经胶质瘤干细胞的标志物CD44的表达存在相关性；MKNK1和CD44的共表达能够预测多形性成胶质细胞瘤病人的不良预后。
研究人员利用病人来源细胞建立的细胞系进行研究发现使用肿瘤治疗药物LY2801653（merestinib）对MNK进行抑制能够进一步抑制真核翻译起始因子4E（eIF4E）的磷酸化水平，eIF4E是MNK诱导癌细胞进行mRNA翻译的一个重要执行因子，同时也是癌细胞转化的一个标记物。
更为重要的是，研究人员通过极限稀释分析方法发现merestinib能够抑制神经胶质瘤干细胞形成的神经球的生长，这表明肿瘤治疗药物merestinib可以作用于神经胶质瘤干细胞，有望解决这种致命脑瘤的治疗抵抗和复发难题。
研究人员通过颅骨内异种移植小鼠模型评估了merestinib在体内条件下的治疗效果，结果观察到接受药物治疗的小鼠其整体生存率得到了提高。
这些临床前结果表明通过药物学方法抑制MNK活性可能是靶向治疗间叶细胞样多形性成胶质细胞瘤及其神经胶质瘤干细胞群体的潜在方法，该研究为攻克这种致命脑瘤找到了新的靶点。
Jonathan B Bell, Frank Eckerdt, Kristen Alley, Lisa P Magnusson, Hridi Hussain, Yingtao Bi, Ahmet Dirim Arslan, Jessica Clymer, Angel A. Alvarez, Stewart Goldman, Shi-Yuan Cheng, Ichiro Nakano, Craig Horbinski, Ramana V. Davuluri, C. David James, Leonidas C Platanias
Glioblastoma multiforme (GBM) remains the deadliest malignant brain tumor, with glioma stem cells (GSCs) contributing to treatment resistance and tumor recurrence. We have identified MAPK-interacting kinases (MNKs) as potential targets for the GSC population in GBM. Isoform-level subtyping using The Cancer Genome Atlas (TCGA) revealed that both MNK genes (MKNK1 and MKNK2) are upregulated in mesenchymal GBM as compared to other subtypes. Expression of MKNK1 is associated with increased glioma grade and correlated with the mesenchymal GSC marker, CD44; and co-expression of MKNK1 and CD44 predicts poor survival in GBM. In established and patient-derived cell lines, pharmacological MNK inhibition using LY2801653 (merestinib) inhibited phosphorylation of the eukaryotic translation initiation factor 4E (eIF4E), a crucial effector for MNK induced mRNA translation in cancer cells and a marker of transformation. Importantly, merestinib inhibited growth of GSCs grown as neurospheres as determined by extreme limiting dilution analysis (ELDA). When the effects of merestinib were assessed in vivo using an intracranial xenograft mouse model, improved overall survival was observed in merestinib-treated mice. Taken together, these data provide strong preclinical evidence that pharmacological MNK inhibition targets mesenchymal GBM and its GSC population. Implications: These findings raise the possibility of MNK inhibition as a viable therapeutic approach to target the mesenchymal subtype of GBM.