2016年7月11日訊 /生物谷BIOON/ --近日，來自美國西北大學的研究人員在國際學術期刊Molecular Cancer Research上發表了一篇文章，他們通過研究找到了治療多形性成膠質細胞瘤及神經膠質瘤幹細胞的潛在靶點。多形性成膠質細胞瘤目前仍然是最致命的惡性腦瘤，而神經膠質瘤幹細胞會促進治療抵抗和腫瘤復發。
在這項最新研究中，研究人員發現MAPK作用激酶（MNK）是治療多形性成膠質細胞瘤中神經膠質瘤幹細胞群體的潛在靶點。研究分析表明相比於其他疾病亞型來說，間葉細胞樣多形性成膠質細胞瘤的兩個MNK基因（MKNK1和MKNK2）均發生表達上調。
MKNK1的表達與神經膠質瘤級別增加有關，還與間葉細胞樣神經膠質瘤幹細胞的標誌物CD44的表達存在相關性；MKNK1和CD44的共表達能夠預測多形性成膠質細胞瘤病人的不良預後。
研究人員利用病人來源細胞建立的細胞系進行研究發現使用腫瘤治療藥物LY2801653（merestinib）對MNK進行抑制能夠進一步抑制真核翻譯起始因子4E（eIF4E）的磷酸化水平，eIF4E是MNK誘導癌細胞進行mRNA翻譯的一個重要執行因子，同時也是癌細胞轉化的一個標記物。
更為重要的是，研究人員通過極限稀釋分析方法發現merestinib能夠抑制神經膠質瘤幹細胞形成的神經球的生長，這表明腫瘤治療藥物merestinib可以作用於神經膠質瘤幹細胞，有望解決這種致命腦瘤的治療抵抗和復發難題。
研究人員通過顱骨內異種移植小鼠模型評估了merestinib在體內條件下的治療效果，結果觀察到接受藥物治療的小鼠其整體生存率得到了提高。
這些臨床前結果表明通過藥物學方法抑制MNK活性可能是靶向治療間葉細胞樣多形性成膠質細胞瘤及其神經膠質瘤幹細胞群體的潛在方法，該研究為攻克這種致命腦瘤找到了新的靶點。（生物谷Bioon.com）
相關會議推薦
2016（第八屆）幹細胞技術與臨床轉化論壇
會議時間：2016.09.23-2016.09.24 會議地點：北京
會議詳情： http://www.bioon.com/z/2016stemcell/
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DOI: 10.1158/1541-7786.MCR-16-0172
MNK Inhibition Disrupts Mesenchymal Glioma Stem Cells and Prolongs Survival in a Mouse Model of Glioblastoma
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.