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Target Inhibition Networks: Predicting Selective Combinations of Druggable Targets to Block Cancer Survival Pathways

Jing Tang, Leena Karhinen, Tao Xu, Agnieszka Szwajda, Bhagwan Yadav, Krister Wennerberg, Tero Aittokallio, Frederick P. Roth
2013 PLoS Computational Biology  
and their targets to maximally inhibit multiple survival pathways in a given cancer type.  ...  not only such druggable kinase targets that are essential for cancer survival either individually or in combination, but also synergistic interactions indicative of nonadditive drug efficacies.  ...  Acknowledgments We thank the authors of PKIM approach, Ranadip Pal and Noah Berlow, for sharing their code and experience, and Sawan Kumar Jha, the Biocenter Finland Drug Discovery and Chemical Biology  ... 
doi:10.1371/journal.pcbi.1003226 pmid:24068907 pmcid:PMC3772058 fatcat:ijqxgzntjffppaymzqizp7ykry

Validation of a network-based strategy for the optimization of combinatorial target selection in breast cancer therapy: siRNA knockdown of network targets in MDA-MB-231 cells as an in vitro model for inhibition of tumor development

Tatiana M. Tilli, Nicolas Carels, Jack A. Tuszynski, Manijeh Pasdar
2016 OncoTarget  
This approach increases the ability to identify not only druggable hubs as essential targets for cancer survival, but also interactions most susceptible to synergistic drug action.  ...  Modulation of cancer networks by anticancer drugs may alter the response of malignant cells and/or drive network re-organization into the inhibition of cancer progression.  ...  ACKNOWLEDGMENTS CONFLICTS OF INTEREST The authors declare that they have no competing interests.  ... 
doi:10.18632/oncotarget.11055 pmid:27527857 pmcid:PMC5325356 fatcat:a3pnngvsxfb6pdv7evsbaiyiaa

Transcription Factor Inhibition: Lessons Learned and Emerging Targets

Andrew Chen, Angela N. Koehler
2020 Trends in Molecular Medicine  
Their activity is frequently deregulated in disease and targeting this class of proteins is a major focus of interest.  ...  We also discuss the progress so far on transcription factors recently nominated by genome-scale loss-of-function screens from the cancer dependency map project.  ...  Inhibition of transcription factor activity 545 can lead to selective killing of cancer cells compared to normal cells.  ... 
doi:10.1016/j.molmed.2020.01.004 pmid:32359481 pmcid:PMC7198608 fatcat:5fxhwysbtrdabnlb3xlh6zcqsq

Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models

Lucia Nappi, Adeleke H. Aguda, Nader Al Nakouzi, Barbara Lelj-Garolla, Eliana Beraldi, Nada Lallous, Marisa Thi, Susan Moore, Ladan Fazli, Dulguun Battsogt, Sophie Stoffeliene, Fuqiang Ban (+9 others)
2019 Journal of Clinical Investigation  
responses to overcome resistance to inhibitors of oncogenic pathway signaling.  ...  Ivermectin directly binds this pocket to inhibit MAPKAP2-mediated HSP27 phosphorylation and depolymerization, thereby blocking HSP27-regulated survival signaling and client-oncoprotein interactions.  ...  HSP27 modulates cancer cell sensitivity to targeted drugs by regulating diverse survival pathways.  ... 
doi:10.1172/jci130819 pmid:31845908 fatcat:v24bjgprkzebrefy2ldtgded7i

Targeted Blockade of JAK/STAT3 Signaling Inhibits Ovarian Carcinoma Growth

G. Gritsina, F. Xiao, S. W. O'Brien, R. Gabbasov, M. A. Maglaty, R.-H. Xu, R. J. Thapa, Y. Zhou, E. Nicolas, S. Litwin, S. Balachandran, L. J. Sigal (+2 others)
2015 Molecular Cancer Therapeutics  
We hypothesized that therapeutic targeting of the JAK/STAT3 pathway would inhibit tumor growth by direct effects on ovarian carcinoma cells and by inhibition of cells in the tumor microenvironment (TME  ...  Taken together, our results show pharmacologic inhibition of the JAK2/STAT3 pathway leads to disruption of functions essential for ovarian tumor growth and progression and represents a promising therapeutic  ...  Connolly), and the FCCC Comprehensive Cancer Center Core Grant NCI P30 CA006927 (to R.I.  ... 
doi:10.1158/1535-7163.mct-14-0800 pmid:25646015 pmcid:PMC4394029 fatcat:ljidioo5ozbetmlev5mznsjxgq

A novel mechanism of action of HER2 targeted immunotherapy is explained by inhibition of NRF2 function in ovarian cancer cells

Hilal S. Khalil, Simon P. Langdon, Alexey Goltsov, Tero Soininen, David J. Harrison, James Bown, Yusuf Y. Deeni
2016 OncoTarget  
Nuclear erythroid related factor-2 (NRF2) is known to promote cancer therapeutic detoxification and crosstalk with growth promoting pathways.  ...  These findings demonstrate a novel mechanism and role for NRF2 in mediating the response of cancer cells to the combination of Trastuzumab and Pertuzumab and reinforce the importance of NRF2 in drug resistance  ...  Figure 3 : 3 Inhibition of NRF2 pathway by Retinoic acid (RA) sensitizes ovarian cancer cells to immunotherapeutic agents targeting HER2 by increased ROS and enhanced growth inhibition.  ... 
doi:10.18632/oncotarget.12425 pmid:27713148 pmcid:PMC5342785 fatcat:7w2xjgi575d5hlk4lhn35e7op4

Analysis of Nuclear Encoded Mitochondrial Gene Networks in Cervical Cancer

Cecile Meneur, Sangavi Eswaran, Divya Adiga, Sriharikrishnaa S, Nadeem Khan G, Sandeep Mallya, Sanjiban Chakrabarty, Shama Prasada Kabekkodu
2021 Asian Pacific Journal of Cancer Prevention  
The FEA identified the enrichment of cancer-related pathways, including AMPK and carbon metabolism in cancer. The combined expression of 10 HG has been shown to affect patient survival.  ...  The impact of methylation on NEMG expression were predicted using DNMIVD and UALCAN tools. HCMDB tool was used to predict genes having metastatic potential.  ...  The present study was a part of student thesis (Ms. Cecile Maneur, UG Student, La Rochelle University, France).  ... 
doi:10.31557/apjcp.2021.22.6.1799 pmid:34181336 pmcid:PMC8418845 fatcat:iwiffimkdjbcxjxya4bec65dam

Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures

Giulia Franciosa, Jos G. A. Smits, Sonia Minuzzo, Ana Martinez-Val, Stefano Indraccolo, Jesper V. Olsen
2021 Nature Communications  
Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.  ...  However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to development of resistance, thus  ...  The proteomics technology developments applied was part of a project that has received funding from the European Union's Horizon 2020 research and innovation program under grant agreements: MSmed-686547  ... 
doi:10.1038/s41467-021-22787-9 pmid:33947863 fatcat:o2t5hggq3jd6vjx6dbxgppjqta

RIPK2 Stabilizes c-Myc and is an Actionable Target for Inhibiting Prostate Cancer Metastasis [article]

Yiwu Yan, Bo Zhou, Chen Qian, Alex Vasquez, Avradip Chatterjee, Xiaopu Yuan, Edwin Posadas, Natasha Kyprianou, Beatrice S. Knudsen, Ramachandran Murali, Arkadiusz Gertych, Sungyong You (+2 others)
2020 bioRxiv   pre-print
Targeting RIPK2 inhibits this phosphorylation pathway, and thus promotes the degradation of c-Myc - a potent oncoprotein for which no drugs have been approved for clinical use yet.  ...  These results support targeting RIPK2 for personalized therapy in prostate cancer patients towards improving survival.  ...  Robert Vessella for the tissue microarray that was supported by the Department of Defense Prostate Cancer Biorepository Network (PCBN) (W81XWH-14-2-0183).  ... 
doi:10.1101/2020.05.14.096867 fatcat:qrxhefsygbdthbanumu3tjh3pa

Predicting targeted drug combinations based on Pareto optimal patterns of coexpression network connectivity

Nadia M Penrod, Casey S Greene, Jason H Moore
2014 Genome Medicine  
Here we introduce a new paradigm for the design of combination therapy treatment strategies that exploits the tumor adaptive process to identify context-dependent essential genes as druggable targets.  ...  However, tumors are dynamic systems that readily adapt to these agents activating alternative survival pathways as they evolve resistant phenotypes.  ...  Acknowledgments This work was supported by National Institutes of Health grants LM009012 and LM010098. The publication costs for this article were funded by JM.  ... 
doi:10.1186/gm550 pmid:24944582 pmcid:PMC4062052 fatcat:kxiqgq7birfwzmvssm43f7euo4

Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia

Xi Jiang, Chao Hu, Kyle Ferchen, Ji Nie, Xiaolong Cui, Chih-Hong Chen, Liting Cheng, Zhixiang Zuo, William Seibel, Chunjiang He, Yixuan Tang, Jennifer R. Skibbe (+22 others)
2017 Nature Communications  
Our results highlight the therapeutic potential of targeting the STAT/TET1 axis by selective inhibitors in AML treatment.  ...  UC-514321, a structural analog of NSC-370284, exhibited a more potent therapeutic effect and prolonged the median survival of TET1-high AML mice over three fold.  ...  Acknowledgements The authors are grateful to Drs Junlin Guan, Saijuan Chen and Ruibao Ren for their constructive comments. We also thank Dr Xiang Zhang (supported by University of  ... 
doi:10.1038/s41467-017-02290-w pmid:29235481 pmcid:PMC5727390 fatcat:hohmqgc3w5g3ji7bopnx2zccsy

Potential Targets' Analysis Reveals Dual PI3K/mTOR Pathway Inhibition as a Promising Therapeutic Strategy for Uterine Leiomyosarcomas—an ENITEC Group Initiative

Tine Cuppens, Daniela Annibali, An Coosemans, Jone Trovik, Natalja ter Haar, Eva Colas, Angel Garcia-Jimenez, Koen Van de Vijver, Roy P.M. Kruitwagen, Mariël Brinkhuis, Michal Zikan, Pavel Dundr (+19 others)
2017 Clinical Cancer Research  
Discussion We analyzed a large cohort of samples from uterine sarcoma patients for the expression of selected druggable therapeutic targets, to determine the subgroups for which specific targeted agents  ...  For this reason, we selected a dual PI3K/mTOR inhibitor, BEZ235, also able to block mTORC2.  ... 
doi:10.1158/1078-0432.ccr-16-2149 pmid:28232476 fatcat:qbwx5xvsi5hgzgz2gnsvdfpwl4

Immunomediated Pan-cancer Regulation Networks are Dominant Fingerprints after Treatment of Cell Lines with Demethylation

Manama El Baroudi, Caterina Cinti, Enrico Capobianco
2016 Cancer Informatics  
The most prominent feature that emerges from our integrative network maps, linking pathway landscapes to disease and drug-target associations, refers primarily to a mosaic of immune-system crosslinked  ...  Network inference is a powerful approach to decipher pan-cancer systems dynamics.  ...  Acknowledgments EC wishes to thank the Center for Computational Science at the University of Miami.  ... 
doi:10.4137/cin.s31809 pmid:27147816 pmcid:PMC4849425 fatcat:yq4ax5ga4jfk5ju3ycyphyuutu

Network-based target ranking for polypharmacological therapies

Francesca Vitali, Francesca Mulas, Pietro Marini, Riccardo Bellazzi
2013 Journal of Biomedical Informatics  
Given a complex disease, the method exploits the topological features of the related PPI network to identify possible combinations of hit targets.  ...  With the growing understanding of complex diseases, the focus of drug discovery has shifted from the well-accepted "one target, one drug" model, to a new "multi-target, multi-drug" model, aimed at systemically  ...  Ideally, a good target would regulate the pathway of interest: thus, blocking the target would result in effective medical treatment.  ... 
doi:10.1016/j.jbi.2013.06.015 pmid:23850841 fatcat:7za32r4jqvbgrf4zivk3j36xei

The pseudophosphatase STYX targets the F‐box of FBXW7 and inhibits SCF FBXW7 function

Veronika Reiterer, Cristina Figueras‐Puig, Francois Le Guerroue, Stefano Confalonieri, Manuela Vecchi, Dasaradha Jalapothu, Sandip M Kanse, Raymond J Deshaies, Pier Paolo Di Fiore, Christian Behrends, Hesso Farhan
2016 EMBO Journal  
Loss of function of FBXW7 results in the stabilization of numerous proteins that orchestrate cell proliferation and survival.  ...  We show that STYX binds to the F-box domain of FBXW7 and disables its recruitment into the SCF complex.  ...  Finally, we asked whether the down-regulation of FBXW7, the up-regulation of STYX, or the combination of both has an impact on the survival of breast cancer patients.  ... 
doi:10.15252/embj.201694795 pmid:28007894 pmcid:PMC5286380 fatcat:dd66lnohfnhzdkatha5fe64k5i
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