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dc.contributor.authorKucherlapati, Melanie H.en_US
dc.contributor.authorEsfahani, Shadien_US
dc.contributor.authorHabibollahi, Peimanen_US
dc.contributor.authorWang, Junningen_US
dc.contributor.authorStill, Eric R.en_US
dc.contributor.authorBronson, Roderick T.en_US
dc.contributor.authorMahmood, Umaren_US
dc.contributor.authorKucherlapati, Raju S.en_US
dc.date.accessioned2014-03-01T02:25:23Z
dc.date.issued2013en_US
dc.identifier.citationKucherlapati, Melanie H., Shadi Esfahani, Peiman Habibollahi, Junning Wang, Eric R. Still, Roderick T. Bronson, Umar Mahmood, and Raju S. Kucherlapati. 2013. “Genotype Directed Therapy in Murine Mismatch Repair Deficient Tumors.” PLoS ONE 8 (7): e68817. doi:10.1371/journal.pone.0068817. http://dx.doi.org/10.1371/journal.pone.0068817.en
dc.identifier.issn1932-6203en
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11855892
dc.description.abstractThe PI3K/AKT/mTOR pathway has frequently been found activated in human tumors. We show that in addition to Wnt signaling dysfunction, the PI3K/AKT/mTOR pathway is often upregulated in mouse Msh2−/− initiated intestinal tumors. NVP-BEZ235 is a dual PI3K/mTOR inhibitor toxic to many cancer cell lines and currently involved in clinical trials. We have treated two mouse models involving Msh2 that develop small intestinal and/or colonic tumors with NVP-BEZ235, and a subset of animals with NVP-BEZ235 and MEK inhibitor ADZ4266. The disease phenotype has been followed with pathology, 18F FDG PET imaging, and endoscopy. Intestinal adenocarcinomas are significantly decreased in multiplicity by both drug regimens. The majority of tumors treated with combined therapy regress significantly, while a small number of highly progressed tumors persist. We have examined PTEN, AKT, MEK 1&2, MAPK, S6K, mTOR, PDPK1, and Cyclin D1 and find variable alterations that include downregulation of PTEN, upregulation of AKT and changes in its phosphorylated forms, upregulation of pMEK 1&2, p42p44MAPK, pS6K, and Cyclin D1. Apoptosis has been found intact in some tumors and not in others. Our data indicate that NVP-BEZ235 alone and in combination with ADZ4266 are effective in treating a proportion of colorectal cancers, but that highly progressed resistant tumors grow in the presence of the drugs. Pathways upregulated in some resistant tumors also include PDPK1, suggesting that metabolic inhibitors may also be useful in treating these tumors.en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.relation.isversionofdoi:10.1371/journal.pone.0068817en
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3720855/pdf/en
dash.licenseLAAen_US
dc.subjectBiologyen
dc.subjectBiochemistryen
dc.subjectDrug Discoveryen
dc.subjectGeneticsen
dc.subjectAnimal Geneticsen
dc.subjectCancer Geneticsen
dc.subjectGenetic Mutationen
dc.subjectMolecular Geneticsen
dc.subjectHistologyen
dc.subjectImmunologyen
dc.subjectImmunologic Techniquesen
dc.subjectImmunohistochemical Analysisen
dc.subjectModel Organismsen
dc.subjectAnimal Modelsen
dc.subjectMouseen
dc.subjectMolecular Cell Biologyen
dc.subjectRadiobiologyen
dc.subjectMedicineen
dc.subjectGastroenterology and Hepatologyen
dc.subjectColonen
dc.subjectColonoscopyen
dc.subjectGastrointestinal Cancersen
dc.subjectRadiologyen
dc.subjectNuclear Medicineen
dc.subjectPET imagingen
dc.titleGenotype Directed Therapy in Murine Mismatch Repair Deficient Tumorsen
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden
dc.relation.journalPLoS ONEen
dash.depositing.authorKucherlapati, Melanie H.en_US
dc.date.available2014-03-01T02:25:23Z
dc.identifier.doi10.1371/journal.pone.0068817*
dash.authorsorderedfalse
dash.contributor.affiliatedEsfahani, Shadi
dash.contributor.affiliatedMahmood, Umar
dash.contributor.affiliatedKucherlapati, Melanie
dash.contributor.affiliatedKucherlapati, Raju
dash.contributor.affiliatedBronson, Roderick


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