47 research outputs found
Customizing the therapeutic response of signaling networks to promote antitumor responses by drug combinations
No full textThis work was supported by grants from Breakthrough Breast Cancer and Scottish Funding Council (SRDG), and personal support to Alexey Goltsov from Scottish Informatics and Computer Science Alliance (SICSA) and to James Bown from The Northwood Trust.Drug resistance, de novo and acquired, pervades cellular signaling networks (SNs) from one signaling motif to another as a result of cancer progression and/or drug intervention. This resistance is one of the key determinants of efficacy in targeted anti-cancer drug therapy. Although poorly understood, drug resistance is already being addressed in combination therapy by selecting drug targets where SN sensitivity increases due to combination components or as a result of de novo or acquired mutations. Additionally, successive drug combinations have shown low resistance potential. To promote a rational, systematic development of combination therapies, it is necessary to establish the underlying mechanisms that drive the advantages of combination therapies, and design methods to determine drug targets for combination regimens. Based on a joint systems analysis of cellular SN response and its sensitivity to drug action and oncogenic mutations, we describe an in silico method to analyze the targets of drug combinations. Our method explores mechanisms of sensitizing the SN through a combination of two drugs targeting vertical signaling pathways. We propose a paradigm of SN response customization by one drug to both maximize the effect of another drug in combination and promote a robust therapeutic response against oncogenic mutations. The method was applied to customize the response of the ErbB/PI3K/PTEN/AKT pathway by combination of drugs targeting HER2 receptors and proteins in the down-stream pathway. The results of a computational experiment showed that the modification of the SN response from hyperbolic to smooth sigmoid response by manipulation of two drugs in combination leads to greater robustness in therapeutic response against oncogenic mutations determining cancer heterogeneity. The application of this method in drug combination co-development suggests a combined evaluation of inhibition effects together with the capability of drug combinations to suppress resistance mechanisms before they become clinically manifest.Peer reviewe
Abstract LB-012: Deoxyglucose and bisphosphonate shows common pathways in its drug repurposed anticancer and anti-infection actions
No full textAbstract
We earlier showed with Systems Biology approach that the genotoxic stress response evoked by cancer, infection, and radiation injury have similarities, particularly at the gastrointestinal tract. This was made possible using biophotonics, and show promise in drug screening opportunities using each of these pathologies as a surrogate model for one another. Using similar molecular Imaging methodology, we showed for the first time binding of osteoporosis drug bisphosphonate to prostate and ovarian cancer tumors and potential drug repurposing candidature. Recently, we presented similar drug re-tasking potential of 2-Deoxyglucose (2-DG) in anti-infection. Here, our data demonstrating mitigation of citrobacter rodentium infection by dietary treatment by 2-DG (0.4%), were analyzed with the bisphosphonate anti-infection response to enteric bacterial pathogens data reported elsewhere. Based on these results, a systems approach analysis is developed and presented demonstrating cross-talk and communication between different cells and integrated responses to pathogens and disease by 2-DG and bisphosphonate in anticancer and anti-infection actions. A role in EGFR signaling and modulation in the infiltration immune response cells by these two dissimilar compounds play a profound bridging event in anticancer and anti-infection activities. These system biology strategies will provide opportunities for drug repurposing in personalized cancer therapy and in anti-microbial management during cancer treatment. Also pave way for safer drugs in prevention and therapy of HER family-driven cancers.
Citation Format: Rao V. Papineni, Shahid Umar, Alexey Goltsov, Ishfaq Ahmed. Deoxyglucose and bisphosphonate shows common pathways in its drug repurposed anticancer and anti-infection actions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-012. doi:10.1158/1538-7445.AM2017-LB-012</jats:p
Three Grand Challenges in High Throughput Omics Technologies
No full textOver the years, next-generation sequencing (NGS) and advanced bioinformatics approaches have allowed the transition of genomic assays into translational practices [...
Narratives for drug design
No full textWe explore the role of narratives of complex systems in anti-cancer drug design. We set out the value of narratives relating to cancer in promoting awareness of risky behaviour and in supporting decision-making regarding treatment options. We present cancer as a dysregulated, complex system that has emergent behaviours at multiple scales, and is governed by dynamical spatio-temporal processes. We show that this system changes structure and function in response to anti-cancer drugs, and explain that these changes are sufficiently complex to impede effective drug design. We pose what narrative might offer to support the process of drug design, providing an example of work done to date that might serve as a foundation for narrating complexity. We suggest ways of using this work combined with that of others to begin to consider narrating drug design
Systems analysis of drug-induced receptor tyrosine kinase reprogramming following targeted mono- and combination anti-cancer therapy
No full textThe receptor tyrosine kinases (RTKs) are key drivers of cancer progression and targets for drug therapy. A major challenge in anti-RTK treatment is the dependence of drug effectiveness on co-expression of multiple RTKs which defines resistance to single drug therapy. Reprogramming of the RTK network leading to alteration in RTK co-expression in response to drug intervention is a dynamic mechanism of acquired resistance to single drug therapy in many cancers. One route to overcome this resistance is combination therapy. We describe the results of a joint in silico, in vitro, and in vivo investigations on the efficacy of trastuzumab, pertuzumab and their combination to target the HER2 receptors. Computational modelling revealed that these two drugs alone and in combination differentially suppressed RTK network activation depending on RTK co-expression. Analyses of mRNA expression in SKOV3 ovarian tumour xenograft showed up-regulation of HER3 following treatment. Considering this in a computational model revealed that HER3 up-regulation reprograms RTK kinetics from HER2 homodimerisation to HER3/HER2 heterodimerisation. The results showed synergy of the trastuzumab and pertuzumab combination treatment of the HER2 overexpressing tumour can be due to an independence of the combination effect on HER3/HER2 composition when it changes due to drug-induced RTK reprogramming.Peer reviewe
In Silico Screening of Nonsteroidal Anti-Inflammatory Drugs and Their Combined Action on Prostaglandin H Synthase-1
No full textThe detailed kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was applied to in silico screening of dose-dependencies for the different types of nonsteroidal anti-inflammatory drugs (NSAIDs), such as: reversible/irreversible, nonselective/selective to PGHS-1/PGHS-2 and time dependent/independent inhibitors (aspirin, ibuprofen, celecoxib, etc.) The computational screening has shown a significant variability in the IC50s of the same drug, depending on different in vitro and in vivo experimental conditions. To study this high heterogeneity in the inhibitory effects of NSAIDs, we have developed an in silico approach to evaluate NSAID action on targets under different PGHS-1 microenvironmental conditions, such as arachidonic acid, reducing cofactor, and peroxide concentrations. The designed technique permits translating the drug IC50, obtained in one experimental setting to another, and predicts in vivo inhibitory effects based on the relevant in vitro data. For the aspirin case, we elucidated the mechanism underlying the enhancement and reduction (aspirin resistance) of its efficacy, depending on PGHS-1 microenvironment in in vitro/in vivo experimental settings. We also present the results of the in silico screening of the combined action of sets of two NSAIDs (aspirin with ibuprofen, aspirin with celecoxib), and study the mechanism of the experimentally observed effect of the suppression of aspirin-mediated PGHS-1 inhibition by selective and nonselective NSAIDs. Furthermore, we discuss the applications of the obtained results to the problems of standardization of NSAID test assay, dependence of the NSAID efficacy on cellular environment of PGHS-1, drug resistance, and NSAID combination therapy
The Society of Orthodox Parishes of Petrograd and its Province (1920–1922): the Experience of Sobornost under Persecution
No full textThis article is devoted to the history of the Society of Orthodox Parishes of Petrograd and its Province — a public organization registered by the Soviet government in 1920, which during its 18 months of existence united around 70 parishes of the Petrograd diocese. In 1922, it was administratively dissolved, and its board members found themselves at the centre of accusations of resisting the seizure of church valuables. In addition to the general issues that have been considered to a greater or lesser extent in historiography (the circumstances of the Society’s emergence, its purpose, structure, and main activities), in this article the author explores the founders’ ecclesiological views, finding that their key category for conceiving of church life was sobornost. The author also focuses on the peculiarities of the Society’s legal status and its actual position within the contexts of life within the church and under Soviet legislation in the early 1920s. Here, for the first time, the question of the organization’s relationship with the Petrograd Diocesan Council is posed, and analysis leads us to conclude that there was a conflict between the agencies of diocesan administration and the social movement within the church, which was clearly manifest in the late 1910s and early 1920s. The Society’s potential was realized after the liquidation of the Diocesan Council, when as a group free from the reins of the diocesan administration system, it turned out to be the largest and most representative church association in Petrograd, striving to influence a whole range of issues related to parish life. The article also attempts to outline the connection between the Society and preceding and subsequent phenomena within post-revolutionary church life, including the Local Council of 1917–1918 and the Renovationist movement, whose participants were directly related to the Society
Diagnostics (Basel)
No full textBreast cancer prevention is an important health issue for women worldwide. In this study, we compared the conventional breast cancer screening exams of mammography and ultrasound with the novel approaches of passive microwave radiometry (MWR) and microRNA (miRNA) analysis. While mammography screening dynamics could be completed in 3-6 months, MWR provided a prediction in a matter of weeks or even days. Moreover, MWR has the potential of being complemented with miRNA diagnostics to further improve its predictive quality. These novel techniques can be used alone or in conjunction with more established techniques to improve early breast cancer diagnosis
Cycle Network Model of Prostaglandin H Synthase-1
No full textThe kinetic model of Prostaglandin H Synthase-1 (PGHS-1) was developed to investigate its complex network kinetics and non-steroidal anti-inflammatory drugs (NSAIDs) efficacy in different in vitro and in vivo conditions. To correctly describe the complex mechanism of PGHS-1 catalysis, we developed a microscopic approach to modelling of intricate network dynamics of 35 intraenzyme reactions among 24 intermediate states of the enzyme. The developed model quantitatively describes interconnection between cyclooxygenase and peroxidase enzyme activities; substrate (arachidonic acid, AA) and reducing cosubstrate competitive consumption; enzyme self-inactivation; autocatalytic role of AA; enzyme activation threshold; and synthesis of intermediate prostaglandin G2 (PGG2) and final prostaglandin H2 (PGH2) products under wide experimental conditions. In the paper, we provide a detailed description of the enzyme catalytic cycle, model calibration based on a series of in vitro kinetic data, and model validation using experimental data on the regulatory properties of PGHS-1. The validated model of PGHS-1 with a unified set of kinetic parameters is applicable for in silico screening and prediction of the inhibition effects of NSAIDs and their combination on the balance of pro-thrombotic (thromboxane) and anti-thrombotic (prostacyclin) prostaglandin biosynthesis in platelets and endothelial cells expressing PGHS-1
