Abstract
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.
Highlights
Though 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
We aim to systematically investigate potential activated core signaling pathways in ovarian cancer sub-groups by uncovering the up-stream signaling pathways of activated transcription factors (TFs), and identify all available FDA approved drugs targeting on these up-stream signaling and Transcription factor (TF)
The TF-Target regulatory network was downloaded from the supplemental material of reference [17], which was derived from the TF binding site predictions for all target genes from TRANSFAC (v7.4) [18]
Summary
Though 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 oncogenic molecular signaling of ovarian cancer are complicated and remain unclear, and there is a lack of effective targeted therapies for ovarian cancer treatment. In United States, ovarian cancer is the fifth leading cause of cancer-related death in female [1], which accounts for 2.5% of all cancers in female, whereas, 5% of all cancer death in female [2]. The high death rate (< 50% of 5 year survival rate) is mainly because of the late diagnosis and aggressive high grade serous carcinoma [2, 3]. Novel targeted therapies and synergistic drug combinations are needed for ovarian cancer
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