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恶性外周神经鞘瘤的基因组和分子特征表明 IGF1R 通路是治疗的主要靶点。

Genomic and molecular characterization of malignant peripheral nerve sheath tumor identifies the IGF1R pathway as a primary target for treatment.

机构信息

Departments of Bone and Soft Tissue Tumor, Pathology, and Epidemiology and Biostatistics, Tianjin Medical University Cancer Hospital and Institute, Tianjin, China.

出版信息

Clin Cancer Res. 2011 Dec 15;17(24):7563-73. doi: 10.1158/1078-0432.CCR-11-1707. Epub 2011 Oct 31.

DOI:10.1158/1078-0432.CCR-11-1707
PMID:22042973
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3243813/
Abstract

PURPOSE

Malignant peripheral nerve sheath tumor (MPNST) is a rare sarcoma that lacks effective therapeutic strategies. We gain insight into the most recurrent genetically altered pathways with the purpose of scanning possible therapeutic targets.

EXPERIMENTAL DESIGN

We conducted a microarray-based comparative genomic hybridization profiling of two cohorts of primary MPNST tissue samples including 25 patients treated at The University of Texas MD Anderson Cancer Center and 26 patients from Tianjin Cancer Hospital. Immunohistochemistry (IHC) and cell biology detection and validation were carried out on human MPNST tissues and cell lines.

RESULTS

Genomic characterization of 51 MPNST tissue samples identified several frequently amplified regions harboring 2,599 genes and regions of deletion including 4,901 genes. At the pathway level, we identified a significant enrichment of copy number-altering events in the insulin-like growth factor 1 receptor (IGF1R) pathway, including frequent amplifications of the IGF1R gene itself. To validate the IGF1R pathway as a potential target in MPNSTs, we first confirmed that high IGF1R protein correlated with worse tumor-free survival in an independent set of samples using IHC. Two MPNST cell lines (ST88-14 and STS26T) were used to determine the effect of attenuating IGF1R. Inhibition of IGF1R in ST88-14 cells using siRNAs or an IGF1R inhibitor, MK-0646, led to significant decreases in cell proliferation, invasion, and migration accompanied by attenuation of the PI3K/AKT and mitogen-activated protein kinase pathways.

CONCLUSION

These integrated genomic and molecular studies provide evidence that the IGF1R pathway is a potential therapeutic target for patients with MPNST.

摘要

目的

恶性外周神经鞘瘤(MPNST)是一种罕见的肉瘤,缺乏有效的治疗策略。我们深入了解最常见的遗传改变途径,以期寻找可能的治疗靶点。

实验设计

我们对两个队列的原发性 MPNST 组织样本进行了基于微阵列的比较基因组杂交分析,其中包括在德克萨斯大学 MD 安德森癌症中心治疗的 25 名患者和天津肿瘤医院的 26 名患者。我们对人 MPNST 组织和细胞系进行了免疫组织化学(IHC)和细胞生物学检测和验证。

结果

51 个 MPNST 组织样本的基因组特征鉴定出了几个包含 2599 个基因的频繁扩增区域和包含 4901 个基因的缺失区域。在通路水平上,我们发现胰岛素样生长因子 1 受体(IGF1R)通路中的拷贝数改变事件显著富集,包括 IGF1R 基因本身的频繁扩增。为了验证 IGF1R 通路作为 MPNST 中的一个潜在靶点,我们首先使用 IHC 在一组独立样本中证实了高 IGF1R 蛋白与无肿瘤生存时间更差相关。我们使用两种 MPNST 细胞系(ST88-14 和 STS26T)来确定抑制 IGF1R 的效果。使用 siRNAs 或 IGF1R 抑制剂 MK-0646 抑制 ST88-14 细胞中的 IGF1R,可导致细胞增殖、侵袭和迁移显著减少,同时减弱 PI3K/AKT 和丝裂原激活蛋白激酶途径。

结论

这些综合的基因组和分子研究为 IGF1R 通路是 MPNST 患者的潜在治疗靶点提供了证据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28c/3243813/9e9f1c4ab36b/nihms335989f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28c/3243813/4896a0f585aa/nihms335989f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28c/3243813/db40063e1eab/nihms335989f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28c/3243813/9e9f1c4ab36b/nihms335989f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28c/3243813/4896a0f585aa/nihms335989f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28c/3243813/31dc6cb7b064/nihms335989f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28c/3243813/99e7c6153b0c/nihms335989f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28c/3243813/db40063e1eab/nihms335989f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c28c/3243813/9e9f1c4ab36b/nihms335989f5.jpg

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