Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting notch signaling

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dc.contributor.authorWeir, Scott James
dc.contributor.authorDandawate, Prasad
dc.contributor.authorRamamoorthy, Prabhu
dc.contributor.authorRanjarajan, Parthasarathy
dc.contributor.authorWood, Robyn
dc.contributor.authorBrinker, Amanda
dc.contributor.authorAnant, Shrikant
dc.contributor.authorTanol, Mehmet
dc.contributor.authorStanding, David
dc.contributor.authorBhattacharyya, Sangita
dc.contributor.authorWoolbright, Benjamin L.
dc.contributor.authorHam, Tammy
dc.contributor.authorMcCulloch, William
dc.contributor.authorDalton, Michael
dc.contributor.authorReed, Gregory A.
dc.contributor.authorBaltezor, Michael J.
dc.contributor.authorJensen, Roy A.
dc.date.accessioned2021-05-15T12:42:25Z
dc.date.available2021-05-15T12:42:25Z
dc.date.issued2020
dc.departmentEczacılık Fakültesien_US
dc.descriptionAACR Annual Meeting -- JUN 22-24, 2020 -- ELECTR NETWORK
dc.description.abstractCiclopirox (CPX) is an FDA-approved topical antifungal agent that has demonstrated preclinical anticancer activity in a number of solid and hematologic malignancies. Its clinical utility as an oral anticancer agent, however, is limited by poor oral bioavailability and gastrointestinal toxicity. Fosciclopirox, the phosphoryloxymethyl ester of CPX (Ciclopirox Prodrug, CPXPOM), selectively delivers the active metabolite, CPX, to the entire urinary tract following parenteral administration. We characterized the activity of CPX-POM and its major metabolites in in vitro and in vivo preclinical models of high-grade urothelial cancer. CPX inhibited cell proliferation, clonogenicity and spheroid formation, and increased cell cycle arrest at S and G0/G1 phases. Mechanistically, CPX suppressed activation of Notch signaling. Molecular modeling and cellular thermal shift assays demonstrated CPX binding to γ-secretase complex proteins Presenilin 1 and Nicastrin, which are essential for Notch activation. To establish in vivo preclinical proof of principle, we tested fosciclopirox in the validated N-butyl-N-(4- hydroxybutyl) nitrosamine (BBN) mouse bladder cancer model. Once-daily intraperitoneal administration of CPX-POM for four weeks at doses of 235 mg/kg and 470 mg/kg significantly decreased bladder weight, a surrogate for tumor volume, and resulted in a migration to lower stage tumors in CPX-POM treated animals. This was coupled with a reduction in the proliferation index. Additionally, there was a reduction in Presenilin 1 and Hes-1 expression in the bladder tissues of CPXPOM treated animals. Following the completion of the first-in-human Phase 1 trial (NCT03348514), the pharmacologic activity of fosciclopirox is currently being characterized in a Phase 1 expansion cohort study of muscle-invasive bladder cancer patients scheduled for cystectomy (NCT04608045) as well as a Phase 2 trial of newly diagnosed and recurrent urothelial cancer patients scheduled for transurethral resection of bladder tumors (NCT04525131).en_US
dc.description.sponsorshipAmer Assoc Canc Resen_US
dc.identifier.doi10.1158/1538-7445.AM2020-6405
dc.identifier.issn0008-5472
dc.identifier.issn1538-7445
dc.identifier.issue16en_US
dc.identifier.urihttps://doi.org/10.1158/1538-7445.AM2020-6405
dc.identifier.urihttps://hdl.handle.net/20.500.12939/935
dc.identifier.volume80en_US
dc.identifier.wosWOS:000590059307247
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.institutionauthorTanol, Mehmet
dc.language.isoen
dc.publisherAmer Assoc Cancer Researchen_US
dc.relation.ispartofCancer Research
dc.relation.publicationcategoryKonferans Öğesi - Uluslararası - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectFosciclopiroxen_US
dc.subjectUrothelial Canceren_US
dc.titleFosciclopirox suppresses growth of high-grade urothelial cancer by targeting notch signaling
dc.typeConference Object

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