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Conditional robustness analysis for fragility discovery and target identification in biochemical networks and in cancer systems biology

Fortunato Bianconi, Elisa Baldelli, Vienna Luovini, Emanuel F. Petricoin, Lucio Crinò, Paolo Valigi
2015 BMC Systems Biology  
We have applied the proposed framework to the EGFR-IGF1R signal transduction network, a crucial pathway in lung cancer, as an example of Cancer Systems Biology application in drug discovery.  ...  Results: We started from the general definition of robustness introduced by Kitano and applied it to the analysis of dynamical biochemical networks, proposing a new algorithm based on moment independent  ...  Acknowledgements This work was supported by an AIRC grant (15713/2014) to LC, LV and BF. We thank Mustafa Khammash and Gabriele Lillacci for helpful comments and discussion. Author details  ... 
doi:10.1186/s12918-015-0216-5 pmid:26482604 pmcid:PMC4617482 fatcat:pvcknpmgczfqpca5n6cbng5ega

Erratum to: 'Conditional robustness analysis for fragility discovery and target identification in biochemical networks and in cancer systems biology'

Fortunato Bianconi, Elisa Baldelli, Vienna Ludovini, Emanuel F. Petricoin, Lucio Crinò, Paolo Valigi
2016 BMC Systems Biology  
the clock customer support • Convenient online submission • Thorough peer review • Inclusion in PubMed and all major indexing services • Maximum visibility for your research Submit your manuscript at  ...  • We accept pre-submission inquiries • Our selector tool helps you to find the most relevant journal Submit your next manuscript to BioMed Central and we will help you at every step: • We provide round  ... 
doi:10.1186/s12918-016-0267-2 pmid:26935321 pmcid:PMC4774129 fatcat:kjqzlu6zqzfvdphszoolio7pd4

Systems Pharmacology: An Overview [chapter]

Marc R. Birtwistle, Jens Hansen, James M. Gallo, Sreeharish Muppirisetty, Peter Man-Un Ung, Ravi Iyengar, Avner Schlessinger
2016 Systems Pharmacology and Pharmacodynamics  
Dynamic modeling and sensitivity analysis allow the identification of robust and fragile nodes within these modules to identify putative drug targets for single or combinatorial drug treatment.  ...  biology approaches.  ...  Sensitivity Analysis to Assess Fragility A common way to assess such systems-level druggability depends on first casting the biological network in terms of the elementary biochemical reactions that comprise  ... 
doi:10.1007/978-3-319-44534-2_4 fatcat:hnkzgvppa5ehjcqj65vw43fily

Computational systems biology

Hiroaki Kitano
2002 Nature  
Molecular biology has uncovered a multitude of biological facts, such as genome sequences and protein properties, but this alone is not sufficient for interpreting biological systems.  ...  Neither p53 nor the network functions as a tumour suppressor in isolation. In this way, biological systems might be better characterized as symbiotic systems.  ...  For example, current control theory assumes that target values or statuses are provided initially for the systems designer, whereas in biology such targets are created and revised continuously by the system  ... 
doi:10.1038/nature01254 pmid:12432404 fatcat:angnkd6ys5fqpk3a4h6pwytkxa

A Systems Biology Approach Identifies Effective Tumor–Stroma Common Targets for Oral Squamous Cell Carcinoma

Wenxia Meng, Yun Wu, Xin He, Chuanxia Liu, Qinghong Gao, Lin Ge, Lanyan Wu, Ying Liu, Yiqing Guo, Xiaoyu Li, Yurong Liu, Sixiu Chen (+3 others)
2014 Cancer Research  
To employ this concept, we design a systems biology strategy by combining experiment and computation to identify potential common target.  ...  The CTP concept combined with our common target discovery strategy provides a framework for future targeted cancer combinatorial therapies. on April 15, 2017.  ...  We develop a systems biology strategy that combines experiment and computation for identification of the epithelial-mesenchymal common targets (EMCTs).  ... 
doi:10.1158/0008-5472.can-13-2275 pmid:24556718 fatcat:3kav3kmeyrcqfatyflc2rxyxbi

Genetic Screening for Signal Transduction in the Era of Network Biology

Adam Friedman, Norbert Perrimon
2007 Cell  
In contrast to animal-based mutant phenotype assays, recent biochemical and quantitative genetic studies have identified hundreds of potential regulators of known signaling pathways.  ...  We discuss the discrepancy between previous models and new data, put forward a different signaling conceptual framework incorporating time-dependent quantitative contributions, and suggest how this new  ...  Kulkarni, and C. Bakal for helpful comments and H. Dohlman for sharing unpublished data. A.F. is supported by the Medical Scientist Training Program (MSTP).  ... 
doi:10.1016/j.cell.2007.01.007 pmid:17254958 fatcat:od36dyirrje2lhftanmclc4nya

Discovering molecular targets in cancer with multiscale modeling

Zhihui Wang, Veronika Bordas, Thomas S. Deisboeck
2010 Drug development research (Print)  
This novel, integrated approach has the potential to offer a more effective in silico framework for target discovery and represents an important technical step towards systems medicine.  ...  Multiscale modeling is increasingly being recognized as a promising research area in computational cancer systems biology.  ...  Martinos Center for Biomedical Imaging and the Department of Radiology at Massachusetts General Hospital.  ... 
doi:10.1002/ddr.20401 pmid:21572568 pmcid:PMC3092304 fatcat:j2qsvd2pz5dsznhe6qicqzgxom

Metabolic Syndrome and Robustness Tradeoffs

H. Kitano, K. Oda, T. Kimura, Y. Matsuoka, M. Csete, J. Doyle, M. Muramatsu
2004 Diabetes  
Possible therapeutic approaches that target fragility of emergent robustness of the disease state have been discussed.  ...  Because the metabolic syndrome affects multiple interacting organ systems (i.e., it is a systemic disease), a systems-level analysis of disease evolution is essential for both complete elucidation of its  ...  Nevertheless, such a model, combined with theoretical analysis of robustness and fragility of the glucose regulatory system, is a reasonable goal of systems biology efforts.  ... 
doi:10.2337/diabetes.53.suppl_3.s6 pmid:15561923 fatcat:x5geseqrzbepzbrwqtvuu3pwxu

Multi-Level Complexities in Technological Development: Competing Strategies for Drug Discovery [chapter]

Matthias Adam
2010 Boston Studies in the Philosophy of Science  
Due to some fairly general properties of biological networks and the available options for pharmaceutical intervention, drug development is captured in an obstinate methodological dilemma.  ...  The analysis of these strategies reveals serious obstacles to integrating the study of interventive and systems complexity in a systematic, methodical way.  ...  In particular, the robustness and fragility of mechanistic networks is taken to be a feature of complex biological systems that is important for drug action.  ... 
doi:10.1007/978-90-481-9051-5_5 fatcat:5lhsr4oquzasfio6bvlyyx5eiq

Systems biology and its application to the understanding of neurological diseases

Pablo Villoslada, Lawrence Steinman, Sergio E. Baranzini
2009 Annals of Neurology  
Systems biology employs tools developed in physics and mathematics such as nonlinear dynamics, control theory, and modeling of dynamic systems.  ...  Network-based analysis is also challenging the current nosology of neurological diseases.  ...  identification of new biomarkers, 92 a critical step in the process of developing stratified and personalized medicine. 93 For example, network analysis of prostatic cancer identified the androgen receptor  ... 
doi:10.1002/ana.21634 pmid:19260029 fatcat:jv4msfh33vff7biu5hwr7lntce

Small Molecule Inhibition of MERTK Is Efficacious in Non-Small Cell Lung Cancer Models Independent of Driver Oncogene Status

C. T. Cummings, W. Zhang, K. D. Davies, G. D. Kirkpatrick, D. Zhang, D. DeRyckere, X. Wang, S. V. Frye, H. S. Earp, D. K. Graham
2015 Molecular Cancer Therapeutics  
Biochemically, we report the selectivity of UNC2025 for MERTK, and its inhibition of oncogenic downstream signaling.  ...  Our laboratory has previously identified the MERTK receptor tyrosine kinase (RTK) as a potential drug target in multiple cancer types, including NSCLC.  ...  Steric interference can be confirmed by biochemical analysis of the mutant protein and cellular analysis in engineered cell lines.  ... 
doi:10.1158/1535-7163.mct-15-0116 pmid:26162689 pmcid:PMC4704683 fatcat:i7nzfcvgija43ivdmbif4hqyse

Systems approaches and algorithms for discovery of combinatorial therapies

Jacob D. Feala, Jorge Cortes, Phillip M. Duxbury, Carlo Piermarocchi, Andrew D. McCulloch, Giovanni Paternostro
2009 Wiley Interdisciplinary Reviews: Systems Biology and Medicine  
New approaches for designing combinations arising from systems biology are described.  ...  Identification of control parameters presents an extreme challenge due to the combinatorial explosion of control possibilities in combination therapy and to the incomplete knowledge of the systems biology  ...  The consequence of biological robustness in terms of our attempt to control these systems is that specific targets for robustness and fragility must be understood in order to circumvent the intrinsic tendency  ... 
doi:10.1002/wsbm.51 pmid:20836021 fatcat:dakiqntuubgzpabcljmssctwni

A probabilistic approach to identify putative drug targets in biochemical networks

E. Murabito, K. Smallbone, J. Swinton, H. V. Westerhoff, R. Steuer
2010 Journal of the Royal Society Interface  
This novel strategy aims to study how a biochemical network as a whole, rather than its individual components, responds to specific perturbations in different physiological conditions.  ...  AðnormalÞ ¼ 0:01 and C J target AðdiseasedÞ ¼ 0:1, for instance, would be considered preferable to an enzyme B with C J target BðnormalÞ ¼ 0:3 and C J target BðdiseasedÞ ¼ 0:9, as the ratio C J target  ...  We acknowledge the support of the Doctoral Training Center ISBML by EPSRC and BBSRC (EP/F500 009/1), of the Manchester Center of Integrative Systems Biology by BBSRC, EPSRC (BB/C0082191) and additional  ... 
doi:10.1098/rsif.2010.0540 pmid:21123256 pmcid:PMC3104352 fatcat:j7cswz3wjvggnbbt6mxp6odtqi

Metabolic networks of microbial systems

Sumana Bhattacharya, Subhra Chakrabarti, Amiya Nayak, Sanjoy K Bhattacharya
2003 Microbial Cell Factories  
The predictions using network structure, for example, in silico experiments help illustrate the importance of studying the network properties.  ...  The cells are regarded as complex system but their elements unlike complex systems interact selectively and nonlinearly to produce coherent rather than complex behaviors.  ...  As opposed to controlled complex systems where systems designer often provides target values for the system, in biological systems such targets are created by the system and renewed continuously by the  ... 
pmid:12740044 pmcid:PMC155636 fatcat:6g4fklgusnhbhpnyypztzynxha

Advancing drug discovery for neuropsychiatric disorders using patient-specific stem cell models

Stephen J. Haggarty, M. Catarina Silva, Alan Cross, Nicholas J. Brandon, Roy H. Perlis
2016 Molecular and Cellular Neuroscience  
Still, the overall use of iPSC-based human cell models with functional cellular and biochemical assays holds promise for supporting the discovery of next-generation neuropharmacological agents for the  ...  Compelling clinical, social, and economic reasons exist to innovate in the process of drug discovery for neuropsychiatric disorders.  ...  Extending this type of work will undoubtedly aid in the identification of pathways and networks affected by human genetic variation an in doing so provide new targets for therapeutic intervention.  ... 
doi:10.1016/j.mcn.2016.01.011 pmid:26826498 pmcid:PMC5292010 fatcat:byeajr65fndnliwdkurdkrt3zu
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