Fosciclopirox suppresses growth of high-grade urothelial cancer by targeting the \u03b3-secretase complex

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

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).

Highlights

Bladder cancer is the 6th most common solid tumor in the United States with an estimated 83,730 new cases and17,200 deaths in 20211
In vitro studies in the T24 high-grade human urothelial cancer cell line demonstrated that CPX-POM and ciclopirox glucuronide (CPX-G) have little (IC50 > 50 μM) to no anticancer activity
non-muscle-invasive bladder cancer (NMIBC) remains a significant problem with high rates of recurrence and progression to muscle-invasive bladder cancer (MIBC) despite current standard-of-care therapy

Summary

Introduction

Bladder cancer is the 6th most common solid tumor in the United States with an estimated 83,730 new cases and. There are an estimated 699,450 people living with this disease in the United States[2]. The disease has a high risk of recurrence and progression that requires life-long surveillance, making this the most expensive cancer to treat on a per-patient-lifetime-basis[3]. While the overall 5-year survival rate for bladder cancer is. 77%, in those with advanced disease, this rate can be as low as 4%4. Bladder cancer is defined as two diseases, each with different treatment approaches and outcomes.

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Conclusion