神經膠母細胞瘤(Glioblastoma, GBM)是成人腦腫瘤中最常見且最惡性的腫瘤。神經膠母細胞瘤的病人存活率自診斷後的中位數存活時間通常只有約15個月，且易發生治療抗藥性的問題，如最常被使用之化療用藥帝盟多(Temozolomide, Temodar, or TMZ)之抗藥性，使得治療上更為困難並急需尋求其他有效的治療方法。除TMZ的化療之外，標靶治療也是一個在臨床上治療神經膠母細胞瘤的一種方式。然而，依舊難以避免治療抗藥性及無法克服高腫瘤異質性的問題。據近期報導，有研究團隊發現神經膠母細胞瘤能大致分為四種細胞亞型，分別為表現EGFR，PDGFRA，CDK4和NF1的細胞亞型，並且不同型態能同時存在於同一病人體內。因此，這也許能說明為什麼有些標靶藥物於臨床試驗失敗之故，尤其那些對TMZ有抗性的病人。這些證據說明了單一標靶療法似乎無法有效治療神經膠母細胞瘤並急需一個能同時標靶EGFR，PDGFRA，CDK4和NF1的藥物來更有效對抗神經膠母細胞瘤。據報導，HSP90(熱休克蛋白九十)在癌細胞中廣泛的被高度表現並幫助癌細胞所需的致癌蛋白之穩定與摺疊。除此之外，HSP90之抑制劑據報導能下調EGFR、PDGFRA和CDK4在癌細胞之表現量，也指出其能被用來治療具有NF1基因突變的疾病，如神經膠質瘤。據以上這些報導，HSP90抑制劑似乎可能可以做為一個多重標靶藥物去同時標靶GBM中的EGFR、PDGFRA、CDK4和NF1來治療GBM，但相關的文獻討論缺乏完整性。因此在本論文中，一個目前處於臨床二期的HSP90抑制劑NVP-AUY922及源自病人之GBM 細胞P#5和P#5 TMZ-R被用來做相關的探討。研究結果顯示，AUY922 100nM 72h的處理能顯著引起P#5 TMZ-R之細胞凋亡及自噬，並以mRNA以及蛋白質的層次降低GBM細胞亞型中的EGFR、CDK4和NF1之表現量。根據這樣的結果，能為標靶HSP90來同時標靶GBM細胞亞型提供出另一種新的觀點。

Glioblastoma (GBM) is the most malignant cancer in the brain. Patients newly diagnosed with GBM usually receive TMZ (temozolomide) as their first-line treatment, however, resistance is a regular problem and the median survival is merely 15 months or so. On the other hand, GBM is characterized by EGFR and/or PDGFRA amplification or mutation, therefore, target therapy has been applicated in treating GBM as well. However, some EGFR and PDGFRA inhibitors in clinical trials failed to respond in recurrent GBM. Recently, it has been reported that GBM was limited in four cellular states which expressed EGFR, PDGFRA, CDK4, and NF1. Due to these four, it might explain the failure in the clinical trials. All these results indicated that single target therapy may not be enough for treating GBM, as a result, any therapy that can simultaneously target EGFR, PDGFRA, CDK4, and NF1 becomes urgent in GBM. It has been reported that heat shock protein 90 (HSP90) was highly expressed in cancer cells and helped stabilize and fold immature oncoproteins. Besides, it has been reported that HSP90 inhibitors can downregulate EGFR, PDGFRA, and CDK4 in cancer cells and they have the potential in treating tumor with mutation in NF1 gene like gliomas. All these findings make HSP90 inhibitors promising as a multi-target therapy to treat GBM but there is lack of related discussion about simultaneously targeting all GBM subtypes by targeting HSP90. In this study, NVP-AUY922 (AUY922), a novel HSP90 inhibitor in phase II clinical trial, and patient-derived GBM cells P#5 and P#5 TMZ-R were used in the following experiments. Patient-derived GBM cells might reflect the clinical characteristics in GBM. The results here showed AUY922 100nM 72h significantly induced apoptosis and autophagy, but also, successfully downregulated EGFR, CDK4, and NF1 at mRNA and protein level in P#5 TMZ-R GBM cells. These results might give new sight on targeting HSP90 in treating GBM.

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