Candidate Therapeutic Agents for Hepatocellular Cancer Can Be Identified From Phenotype-Associated Gene Expression Signatures
Candidate Therapeutic Agents for Hepatocellular Cancer Can Be Identified From Phenotype-Associated Gene Expression Signatures
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DOI：
10.1002/cncr.24417
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发表时间：
2009-08-15
期刊：
影响因子：
6.2
通讯作者：
Patel, Tushar
中科院分区：
文献类型：
--
作者：
Braconi, Chiara;Meng, Fanyin;Patel, Tushar
背景技术背景：肝细胞癌（HCC）中血管浸润的存在与预后相关，并且是治疗方法和复发或肝内转移的关键决定因素。作者试图确定能够靶向HCC侵袭性表型的候选治疗药物。方法：来自81例HCC患者的与血管侵袭相关的基因表达特征被用于使用连接图筛选与164种生物活性分子相关的453个基因组谱的数据库。候选代理商被确定其逆相关的查询基因签名。在PLC/PRF-S和HepG 2 HCC细胞中实验验证了候选试剂靶向侵袭的功效。结果：与肝癌血管侵袭相关的基因标签包括47个上调和26个下调基因。计算生物信息学分析揭示了几个推定的候选物，包括白藜芦醇和17-烯丙基氨基格尔德霉素（17-AAG）。这两种药物在非细胞毒性浓度下均可降低HCC细胞的侵袭，热休克蛋白90（HSP-90）抑制剂17-AAG可调节多种癌症相关基因的表达，包括ADAMTS 1（查询签名的一部分）和maspin（在HCC中具有肿瘤抑制作用的HSP-90相关蛋白）。结论：通过对表型相关基因表达的计算生物信息学分析，已经确定了作为限制HCC侵袭疗法的进一步评价的候选者。使用基因组分析的表型靶向是药物发现的合理方法。靶向确定的癌症相关表型的治疗策略可以在不详细了解单个下游靶标的情况下鉴定，Cancer 2009;115：3738-48。(C)2009年美国癌症协会。
BACKGROUND: The presence of vascular invasion in hepatocellular cancer (HCC) correlates with prognosis, and is a critical determinant of both the therapeutic approach and the recurrence or intrahepatic metastases. The authors sought to identify candidate therapeutic agents capable of targeting the invasive phenotype in HCC. METHODS: A gene expression signature associated with vascular invasion derived from 81 human cases of HCC was used to screen a database of 453 genomic profiles associated with 164 bioactive molecules using the connectivity map. Candidate agents were identified by their inverse correlation to the query gene signature. The efficacy of the candidate agents to target invasion was experimentally verified in PLC/PRF-S and HepG2 HCC cells. RESULTS: The gene signature associated with vascular invasion in HCC comprised of 47 up-regulated and 26 down-regulated genes. Computational bioinformatics analysis revealed several putative candidates, including resveratrol and 17-allylamino-geldanamycin (17-AAG). Both of these agents reduced HCC cell invasion at noncytotoxic concentrations, 17-AAG, a heat shock protein 90 (HSP-90) inhibitor, was shown to modulate the expression of several diverse cancer-associated genes, including ADAMTS1, part of the query signature, and maspin, an HSP-90-associated protein with a tumor suppressor role in HCC. CONCLUSIONS: Candidates for further evaluation as therapies to limit invasion in HCC have been identified using a computational bioinformatics analysis of phenotype-associated gene expression. Phenotype targeting using genomic profiling is a rational approach for drug discovery. Therapeutic strategies targeting a defined cancer-associated phenotype can be identified without a detailed knowledge of individual downstream targets, Cancer 2009;115:3738-48. (C) 2009 American Cancer Society.