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

Scott J. Weir, Prasad Dandawate, David Standing, Sangita Bhattacharyya, Prabhu Ramamoorthy, Parthasarathy Rangarajan, Robyn Wood, Amanda E. Brinker, Benjamin L. Woolbright, Mehmet Tanol, Tammy Ham, William McCulloch, Michael Dalton, Gregory A. Reed, Michael J. Baltezor, Roy A. Jensen, John A. Taylor, Shrikant Anant

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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).

Original languageEnglish (US)
Article number562
JournalCell Death and Disease
Volume12
Issue number6
DOIs
StatePublished - Jun 2021
Externally publishedYes

Bibliographical note

Funding Information:
Studies were supported by an NIH grant CA182872 to S.A. and S.J.W., and the Institute for Advancing Medical Innovation (IAMI) at the University of Kansas Medical Center, established through a grant provided to SJW by the Ewing Marion Kauffman Foundation. Drug discovery and development resources were provided by the Lead Development and Optimization Shared Resource (LDOSR) of the NCI-supported University of Kansas Cancer Center Core Support Grant (CCSG, CA168524). The Flow Cytometry Core Laboratory is supported by the NIH COBRE (RR016443) and CCSG grants (CA168524).

Publisher Copyright:
© 2021, The Author(s).

Keywords

  • Amyloid Precursor Protein Secretases/metabolism
  • Antifungal Agents/pharmacology
  • Carcinoma, Transitional Cell/drug therapy
  • Ciclopirox/pharmacology
  • Humans
  • Neoplasm Grading

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural

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