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Article: Novel modeling of cancer cell signaling pathways enables systematic drug repositioning for distinct breast cancer metastases

TitleNovel modeling of cancer cell signaling pathways enables systematic drug repositioning for distinct breast cancer metastases
Authors
Issue Date2013
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2013, v. 73 n. 20, p. 6149-6163 How to Cite?
AbstractA new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed specific CSBs for each metastasis that satisfy (i) CSB proteins are activated by the maximal number of enriched signaling pathways specific to a given metastasis, and (ii) CSB proteins are involved in the most differential expressed coding genes specific to each breast cancer metastasis. The identified signaling networks for the three types of breast cancer metastases contain 31, 15, and 18 proteins and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases. We conducted both in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Of special note, we found that the Food and Drug Administration-approved drugs, sunitinib and dasatinib, prohibit brain metastases derived from breast cancer, addressing one particularly challenging aspect of this disease.
Persistent Identifierhttp://hdl.handle.net/10722/200600
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorZhao, Hen_US
dc.contributor.authorJin, Gen_US
dc.contributor.authorRen, Den_US
dc.contributor.authorLiu, Ten_US
dc.contributor.authorChen, Pen_US
dc.contributor.authorWong, Sen_US
dc.contributor.authorLi, Fen_US
dc.contributor.authorFan, YBen_US
dc.contributor.authorRodriguez, Aen_US
dc.contributor.authorChang, Jen_US
dc.contributor.authorWong, STCen_US
dc.date.accessioned2014-08-21T06:52:38Z-
dc.date.available2014-08-21T06:52:38Z-
dc.date.issued2013en_US
dc.identifier.citationCancer Research, 2013, v. 73 n. 20, p. 6149-6163en_US
dc.identifier.issn0008-5472en_US
dc.identifier.urihttp://hdl.handle.net/10722/200600-
dc.description.abstractA new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target-disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed specific CSBs for each metastasis that satisfy (i) CSB proteins are activated by the maximal number of enriched signaling pathways specific to a given metastasis, and (ii) CSB proteins are involved in the most differential expressed coding genes specific to each breast cancer metastasis. The identified signaling networks for the three types of breast cancer metastases contain 31, 15, and 18 proteins and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases. We conducted both in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Of special note, we found that the Food and Drug Administration-approved drugs, sunitinib and dasatinib, prohibit brain metastases derived from breast cancer, addressing one particularly challenging aspect of this disease.en_US
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/en_US
dc.relation.ispartofCancer Researchen_US
dc.subject.meshBrain Neoplasms - drug therapy - metabolism - secondaryen_US
dc.subject.meshBreast Neoplasms - drug therapy - metabolism - pathologyen_US
dc.subject.meshDrug Repositioningen_US
dc.subject.meshLung Neoplasms - drug therapy - metabolism - secondaryen_US
dc.subject.meshModels, Biologicalen_US
dc.titleNovel modeling of cancer cell signaling pathways enables systematic drug repositioning for distinct breast cancer metastasesen_US
dc.typeArticleen_US
dc.identifier.emailChen, P: pkchen@hku.hken_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1158/0008-5472.CAN-12-4617en_US
dc.identifier.pmid24097821en_US
dc.identifier.pmcidPMC4005386en_US
dc.identifier.hkuros232131en_US
dc.identifier.volume73en_US
dc.identifier.issue20en_US
dc.identifier.spage6149en_US
dc.identifier.epage6163en_US
dc.identifier.isiWOS:000325796100008-
dc.publisher.placeUnited Statesen_US

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