Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease-associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease-associated gene signatures (i.e., limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low-survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient-derived xenograft (PDX). Our results demonstrate that by applying multiple disease-associated gene signature methods, we prioritized several drug repurposing candidates for low-survival cancers.

中文翻译：

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三种疾病相关基因特征的特征逆转优先考虑癌症药物新用途候选者

药物再利用前景广阔，因为批准一种药物用于新适应症所需的资源比批准一种新药要少。特征逆转检测与疾病相关基因特征最负相关的药物扰动，以识别可能逆转该特征的药物。我们评估了三种构建疾病相关基因特征的方法（即 limma、DESeq2 和 MultiPLIER）的性能和生物学相关性，并优先考虑了四种低存活率人类癌症的药物再利用候选药物。我们的结果丰富了已用于临床试验或在 PRISM 药物筛选中表现良好的候选药物。此外，我们发现帕米膦酸和尼莫地平（预计对脑肿瘤胶质母细胞瘤（GBM）有效的药物）抑制 GBM 细胞系和从患者来源的异种移植物（PDX）中分离的细胞的生长。我们的结果表明，通过应用多种疾病相关基因特征方法，我们优先考虑了几种针对低存活率癌症的药物再利用候选药物。