Department of Computer Science, Purdue University, West Lafayette, IN, USA.
Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, USA.
Nat Commun. 2024 Aug 24;15(1):7288. doi: 10.1038/s41467-024-51859-9.
Correctly identifying perturbed biological pathways is a critical step in uncovering basic disease mechanisms and developing much-needed therapeutic strategies. However, whether current tools are optimal for unbiased discovery of relevant pathways remains unclear. Here, we create "Benchmark" to critically evaluate existing tools and find that most function sub-optimally. We thus develop the "Pathway Ensemble Tool" (PET), which outperforms existing methods. Deploying PET, we identify prognostic pathways across 12 cancer types. PET-identified prognostic pathways offer additional insights, with genes within these pathways serving as reliable biomarkers for clinical outcomes. Additionally, normalizing these pathways using drug repurposing strategies represents therapeutic opportunities. For example, the top predicted repurposed drug for bladder cancer, a CDK2/9 inhibitor, represses cell growth in vitro and in vivo. We anticipate that using Benchmark and PET for unbiased pathway discovery will offer additional insights into disease mechanisms across a spectrum of diseases, enabling biomarker discovery and therapeutic strategies.
正确识别失调的生物途径是揭示基本疾病机制和开发急需的治疗策略的关键步骤。然而，目前的工具是否最适合于无偏发现相关途径尚不清楚。在这里，我们创建了“基准”来严格评估现有工具，并发现大多数工具的功能都不理想。因此，我们开发了“途径综合工具”（PET），它优于现有方法。通过部署 PET，我们在 12 种癌症类型中识别出了预后途径。PET 识别的预后途径提供了额外的见解，这些途径中的基因可作为临床结果的可靠生物标志物。此外，使用药物再利用策略对这些途径进行归一化代表了治疗机会。例如，膀胱癌的首选预测再利用药物 CDK2/9 抑制剂，可抑制体外和体内的细胞生长。我们预计，使用基准和 PET 进行无偏途径发现将为一系列疾病的疾病机制提供额外的见解，从而实现生物标志物发现和治疗策略。
