Divisions of Experimental Hematology and Cancer Biology, Oncology, and Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, USA.
Clin Cancer Res. 2012 Sep 15;18(18):5020-30. doi: 10.1158/1078-0432.CCR-12-1072. Epub 2012 Jul 18.
Patients with neurofibromatosis type 1 (NF1) develop malignant peripheral nerve sheath tumors (MPNST), which are often inoperable and do not respond well to current chemotherapies or radiation. The goal of this study was to use comprehensive gene expression analysis to identify novel therapeutic targets.
Nerve Schwann cells and/or their precursors are the tumorigenic cell types in MPNST because of the loss of the NF1 gene, which encodes the RasGAP protein neurofibromin. Therefore, we created a transgenic mouse model, CNP-HRas12V, expressing constitutively active HRas in Schwann cells and defined a Ras-induced gene expression signature to drive a Bayesian factor regression model analysis of differentially expressed genes in mouse and human neurofibromas and MPNSTs. We tested functional significance of Aurora kinase overexpression in MPNST in vitro and in vivo using Aurora kinase short hairpin RNAs (shRNA) and compounds that inhibit Aurora kinase.
We identified 2,000 genes with probability of linkage to nerve Ras signaling of which 339 were significantly differentially expressed in mouse and human NF1-related tumor samples relative to normal nerves, including Aurora kinase A (AURKA). AURKA was dramatically overexpressed and genomically amplified in MPNSTs but not neurofibromas. Aurora kinase shRNAs and Aurora kinase inhibitors blocked MPNST cell growth in vitro. Furthermore, an AURKA selective inhibitor, MLN8237, stabilized tumor volume and significantly increased survival of mice with MPNST xenografts.
Integrative cross-species transcriptome analyses combined with preclinical testing has provided an effective method for identifying candidates for molecular-targeted therapeutics. Blocking Aurora kinases may be a viable treatment platform for MPNST.
患有神经纤维瘤病 1 型（NF1）的患者会发展出恶性外周神经鞘瘤（MPNST），这些肿瘤通常无法手术切除，并且对当前的化疗或放疗反应不佳。本研究的目的是使用综合基因表达分析来确定新的治疗靶点。
神经雪旺细胞和/或其前体细胞是 MPNST 的肿瘤发生细胞类型，因为 NF1 基因缺失，该基因编码 RasGAP 蛋白神经纤维瘤蛋白。因此，我们创建了一个转基因小鼠模型 CNP-HRas12V，在雪旺细胞中表达组成性激活的 HRas，并定义了 Ras 诱导的基因表达特征，以驱动贝叶斯因子回归模型分析小鼠和人神经纤维瘤和 MPNST 中的差异表达基因。我们使用 Aurora 激酶短发夹 RNA（shRNA）和抑制 Aurora 激酶的化合物在体外和体内测试了 Aurora 激酶过表达在 MPNST 中的功能意义。
我们确定了 2000 个与神经 Ras 信号有链接概率的基因，其中 339 个在小鼠和人 NF1 相关肿瘤样本中相对于正常神经显著差异表达，包括 Aurora 激酶 A（AURKA）。AURKA 在 MPNST 中过度表达并且基因组扩增，但在神经纤维瘤中没有。Aurora 激酶 shRNA 和 Aurora 激酶抑制剂可阻断 MPNST 细胞在体外的生长。此外，AURKA 选择性抑制剂 MLN8237 可稳定肿瘤体积并显著提高 MPNST 异种移植小鼠的存活率。
整合的跨物种转录组分析结合临床前测试为鉴定分子靶向治疗的候选药物提供了一种有效的方法。阻断 Aurora 激酶可能是治疗 MPNST 的可行治疗平台。
