Agnihotri Sameer, Gugel Isabel, Remke Marc, Bornemann Antje, Pantazis Georgios, Mack Stephen C, Shih David, Singh Sanjay K, Sabha Nesrin, Taylor Michael D, Tatagiba Marcos, Zadeh Gelareh, Krischek Boris
Arthur & Sonia Labatt Brain Tumour Research Centre and.
J Neurosurg. 2014 Dec;121(6):1434-45. doi: 10.3171/2014.6.JNS131433. Epub 2014 Sep 23.
Vestibular schwannomas (VS) are common benign tumors of the vestibular nerve that cause significant morbidity. The current treatment strategies for VS include surgery or radiation, with each treatment option having associated complications and side effects. The transcriptional landscape of schwannoma remains largely unknown.
In this study the authors performed gene-expression profiling of 49 schwannomas and 7 normal control vestibular nerves to identify tumor-specific gene-expression patterns. They also interrogated whether schwannomas comprise several molecular subtypes using several transcription-based clustering strategies. The authors also performed in vitro experiments testing therapeutic inhibitors of over-activated pathways in a schwannoma cell line, namely the PI3K/AKT/mTOR pathway.
The authors identified over 4000 differentially expressed genes between controls and schwannomas with network analysis, uncovering proliferation and anti-apoptotic pathways previously not implicated in VS. Furthermore, using several distinct clustering technologies, they could not reproducibly identify distinct VS subtypes or significant differences between sporadic and germline NF2-associated schwannomas, suggesting that they are highly similar entities. The authors identified overexpression of PI3K/AKT/mTOR signaling networks in their gene-expression study and evaluated this pathway for therapeutic targeting. Testing the compounds BEZ235 and PKI-587, both novel dual inhibitors of PI3K and mTOR, attenuated tumor growth in a preclinical cell line model of schwannoma (HEI-293). In vitro findings demonstrated that pharmacological inhibition of the PI3K/AKT/mTOR pathway with next-generation compounds led to decreased cell viability and increased cell death.
These findings implicate aberrant activation of the PI3K/AKT/mTOR pathway as a molecular mechanism of pathogenesis in VS and suggest inhibition of this pathway as a potential treatment strategy.
前庭神经鞘瘤（VS）是前庭神经常见的良性肿瘤，可导致严重的发病情况。目前VS的治疗策略包括手术或放疗，每种治疗方案都有相关的并发症和副作用。神经鞘瘤的转录图谱在很大程度上仍不为人知。
在本研究中，作者对49例神经鞘瘤和7条正常对照前庭神经进行了基因表达谱分析，以确定肿瘤特异性基因表达模式。他们还使用几种基于转录的聚类策略，探究神经鞘瘤是否包含几种分子亚型。作者还进行了体外实验，在一种神经鞘瘤细胞系中测试过度激活通路的治疗性抑制剂，即PI3K/AKT/mTOR通路。
通过网络分析，作者在对照和神经鞘瘤之间鉴定出4000多个差异表达基因，发现了先前与VS无关的增殖和抗凋亡通路。此外，使用几种不同的聚类技术，他们无法可重复地鉴定出不同的VS亚型，或散发性和种系NF2相关神经鞘瘤之间的显著差异，这表明它们是高度相似的实体。作者在基因表达研究中发现PI3K/AKT/mTOR信号网络过表达，并评估了该通路作为治疗靶点的可能性。测试化合物BEZ235和PKI-587，这两种新型的PI3K和mTOR双重抑制剂，在神经鞘瘤的临床前细胞系模型（HEI-293）中减弱了肿瘤生长。体外研究结果表明，用新一代化合物对PI3K/AKT/mTOR通路进行药理抑制导致细胞活力下降和细胞死亡增加。
这些发现表明PI3K/AKT/mTOR通路的异常激活是VS发病机制的分子机制，并提示抑制该通路作为一种潜在的治疗策略。
