2. Academic Validation
  3. Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting the γ-secretase complex

Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting the γ-secretase complex

  • Cell Death Dis. 2021 May 31;12(6):562. doi: 10.1038/s41419-021-03836-z.
Scott J Weir 1 2 3,  Prasad Dandawate 4,  David Standing 4,  Sangita Bhattacharyya 4,  Prabhu Ramamoorthy 4,  Parthasarathy Rangarajan 4,  Robyn Wood 5,  Amanda E Brinker 4 5,  Benjamin L Woolbright 6,  Mehmet Tanol 7 8,  Tammy Ham 9,  William McCulloch 10,  Michael Dalton 11,  Gregory A Reed 12,  Michael J Baltezor 5 7,  Roy A Jensen 4 13,  John A Taylor 3rd 4 6,  Shrikant Anant 14
Affiliations

Affiliations

  • 1 Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA. sweir@kumc.edu.
  • 2 Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA. sweir@kumc.edu.
  • 3 Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, KS, USA. sweir@kumc.edu.
  • 4 Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
  • 5 Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, KS, USA.
  • 6 Department of Urology, University of Kansas Medical Center, Kansas City, KS, USA.
  • 7 Biotechnology Innovation and Optimization Center, University of Kansas, Lawrence, KS, USA.
  • 8 School of Pharmacy, Istanbul Kemerburgaz University, Istanbul, Turkey.
  • 9 CicloMed LLC, Kansas City, MO, USA.
  • 10 Alba BioPharm Advisors Inc., Durham, NC, USA.
  • 11 The Gnomon Group, Carrboro, NC, USA.
  • 12 Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.
  • 13 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
  • 14 Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA. sanant@kumc.edu.
PMID: 34059639 DOI: 10.1038/s41419-021-03836-z
Abstract

Ciclopirox (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, CPX-POM), 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 CPX-POM 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).

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