Network-based discovery of molecular targeted agent treatments in hepatocellular carcinoma

Fayetörbay, Rumeys
Hepatocellular carcinoma (HCC) is one of the most-deadly cancers and the most common type of primary liver cancer. Multikinase inhibitor Sorafenib is one of FDA approved targeted agents in HCC treatment. PI3K/AKT/mTOR pathway is altered in about 51% of HCC; hence, understanding how Sorafenib and PI3K/AKT/mTOR pathway inhibitors act at signaling level is crucial for targeted therapies and to reveal the off-target effects. In this work, we use gene expression profiles (GEPs) of HCC cells (Huh7 and Mahlavu) which were treated with seven different agents and their combination. Our aim is to reveal the important targets and modulators in agent treatments by inferring the dysregulation of Interactome. In other words, we search for the mechanism of action of the agents in a network context beyond the list of genes. For this purpose, we use the DeMAND (Detecting Mechanism of Action based on Network Dysregulation) algorithm developed by Califano Lab. DeMAND compares GEPs and assesses the change in the individual interactions from weighted interactome obtained from STRING database. As a result, we reconstructed 18 agent-specific networks from each GEPs. Each gene and interaction within these networks have a value signifies how strongly these genes are affected from the chemical network perturbation. Then, we found enriched pathways in each network. We initially compared the networks of single agents and their combination; i.e. PI3Ki-α, Sorafenib and their combined treatment. Then, we compared all networks simultaneously. The simultaneous comparison of the reconstructed networks at gene and pathway levels shows that several pathways and proteins are commonly affected across agent treatments (e.g., Wnt, HIF-1, Notch pathways and MCM proteins, mTOR). On the other hand, some pathways are only affected in a specific agent treatment (e.g., SNARE interactions).


Network-based in silico modeling for drug repurposing and in vitro validation in hepatocellular carcinoma
Nalbat, Esra; Tunçbağ, Nurcan; Cetin-Atalay, Rengul (Orta Doğu Teknik Üniversitesi Enformatik Enstitüsü; 2022-10)
Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed cancer and a leading cause of death worldwide. The hyperactivated cell survival signaling pathways cause resistance to conventional chemotherapeutics so that targeted therapies could extend patient survival for only a few months. Furthermore, there are limited chemotherapeutics for HCC patients due to impaired liver functions. Thus, it is vital to determine repurposed drugs and drug combinations in HCC treatment.
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Ovarian cancer is one of the common cancer types among other oncological diseases. The major causes of this cancer can be listed as age, obesity, hormone therapy, material inheritance and contraceptive pills. Due to its generality and importance, many researches have been conducted from distinct labs about this illness and its plausible causes have been intensively investigated either inmicroarray studies, where just part of the related genes are detected, or in thepairwise correlation analyses between the ...
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The breast and gynecological cancers are two most common fatal cancers’ types in women in the world [1]. In oncological literature, these two cancers types are typically worked together since they are the risk factors of each other if the patient has one of these diseases [2]. In general, the cancers, like the heart diseases, are the systems’ ilnesses in the sense that any malfunctions in the associated transaction pathways cause problems in the activation flow, resulting in tumors. Therefore, the mathemati...
Citation Formats
R. Fayetörbay, “Network-based discovery of molecular targeted agent treatments in hepatocellular carcinoma,” Thesis (M.S.) -- Graduate School of Informatics. Bioinformatics., Middle East Technical University, 2020.