Integrative network analysis identifies potential targets and drugs for ovarian cancer

BMC Medical Genomics

Liwei Zhang¹  Tianyu Zhang²  Fuhai Li³ 

[1] Dalian University of Technology, 116024, Dalian, China;Institute for Informatics (I2), Washington University School of Medicine, Washington University in St. Louis, 63130, St. Louis, MO, USA;Dalian University of Technology, 116024, Dalian, China;Institute for Informatics (I2), Washington University School of Medicine, Washington University in St. Louis, 63130, St. Louis, MO, USA;Department of Pediatrics, Washington University School of Medicine, Washington University in St. Louis, 63130, St. Louis, MO, USA;

关键词: Ovarian cancer;    Core signaling pathways;    Network analysis;    Drug discovery;   

DOI  :  10.1186/s12920-020-00773-2

来源: Springer

【 摘 要 】

BackgroundThough accounts for 2.5% of all cancers in female, the death rate of ovarian cancer is high, which is the fifth leading cause of cancer death (5% of all cancer death) in female. The 5-year survival rate of ovarian cancer is less than 50%. The oncogenic molecular signaling of ovarian cancer are complicated and remain unclear, and there is a lack of effective targeted therapies for ovarian cancer treatment.MethodsIn this study, we propose to investigate activated signaling pathways of individual ovarian cancer patients and sub-groups; and identify potential targets and drugs that are able to disrupt the activated signaling pathways. Specifically, we first identify the up-regulated genes of individual cancer patients using Markov chain Monte Carlo (MCMC), and then identify the potential activated transcription factors. After dividing ovarian cancer patients into several sub-groups sharing common transcription factors using K-modes method, we uncover the up-stream signaling pathways of activated transcription factors in each sub-group. Finally, we mapped all FDA approved drugs targeting on the upstream signaling.ResultsThe 427 ovarian cancer samples were divided into 3 sub-groups (with 100, 172, 155 samples respectively) based on the activated TFs (with 14, 25, 26 activated TFs respectively). Multiple up-stream signaling pathways, e.g., MYC, WNT, PDGFRA (RTK), PI3K, AKT TP53, and MTOR, are uncovered to activate the discovered TFs. In addition, 66 FDA approved drugs were identified targeting on the uncovered core signaling pathways. Forty-four drugs had been reported in ovarian cancer related reports. The signaling diversity and heterogeneity can be potential therapeutic targets for drug combination discovery.ConclusionsThe proposed integrative network analysis could uncover potential core signaling pathways, targets and drugs for ovarian cancer treatment.

【 授权许可】

CC BY