A network based approach to drug repositioning identifies plausible candidates for breast cancer and prostate cancer.
A network based approach to drug repositioning identifies plausible candidates for breast cancer and prostate cancer.
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DOI：
10.1186/s12920-016-0212-7
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发表时间：
2016-07-30
影响因子：
2.7
通讯作者：
DeLisi C
中科院分区：
文献类型：
--
作者：
Chen HR;Sherr DH;Hu Z;DeLisi C
将药物投入商业化所需的高成本和长时间促使人们努力重新利用FDA批准的药物，以找到它们原本不打算使用的新用途，从而降低商业化的总成本，缩短药物发现和可用性之间的滞后。我们报告的发展，测试和应用的一个有前途的新方法重新定位。我们的方法是基于挖掘人类功能连锁网络的药物和疾病基因靶点的负相关模块。该方法考虑了多个信息源，包括基因突变，基因表达，功能连接和模块内基因的接近。该方法用于识别治疗乳腺癌和前列腺癌的候选人。我们发现，（i）FDA批准的乳腺癌药物的召回率（前列腺）癌的比率为20/20（10/11），而临床试验中药物的比率为131/154和82/106;（ii）ROC/AUC性能大大超过可比方法;（iii）初步体外研究表明，在MCF 7和SUM 149癌细胞系中，5/5的候选物具有优于阿霉素的治疗指数上级。我们在候选物介导的生物过程的背景下，在分子水平上简要讨论了候选物的生物学合理性。我们的方法似乎为鉴定能够纠正异常细胞功能的多靶向候选药物提供了希望。特别地，计算性能超过了其他基于CMap的方法，并且体外实验表明，5/5的候选物在MCF 7和SUM 149癌细胞系中具有优于阿霉素的治疗指数上级。该方法有可能提供更有效的药物发现管道。本文的在线版本（doi：10.1186/s12920-016-0212-7）包含补充材料，可供授权用户使用。
The high cost and the long time required to bring drugs into commerce is driving efforts to repurpose FDA approved drugs—to find new uses for which they weren’t intended, and to thereby reduce the overall cost of commercialization, and shorten the lag between drug discovery and availability. We report on the development, testing and application of a promising new approach to repositioning. Our approach is based on mining a human functional linkage network for inversely correlated modules of drug and disease gene targets. The method takes account of multiple information sources, including gene mutation, gene expression, and functional connectivity and proximity of within module genes. The method was used to identify candidates for treating breast and prostate cancer. We found that (i) the recall rate for FDA approved drugs for breast (prostate) cancer is 20/20 (10/11), while the rates for drugs in clinical trials were 131/154 and 82/106; (ii) the ROC/AUC performance substantially exceeds that of comparable methods; (iii) preliminary in vitro studies indicate that 5/5 candidates have therapeutic indices superior to that of Doxorubicin in MCF7 and SUM149 cancer cell lines. We briefly discuss the biological plausibility of the candidates at a molecular level in the context of the biological processes that they mediate. Our method appears to offer promise for the identification of multi-targeted drug candidates that can correct aberrant cellular functions. In particular the computational performance exceeded that of other CMap-based methods, and in vitro experiments indicate that 5/5 candidates have therapeutic indices superior to that of Doxorubicin in MCF7 and SUM149 cancer cell lines. The approach has the potential to provide a more efficient drug discovery pipeline. The online version of this article (doi:10.1186/s12920-016-0212-7) contains supplementary material, which is available to authorized users.