First, RNA-sequencing was performed on the bladder cancer cell lines that were used to allow for molecular subtyping. The 32 selected cell lines represented both non-muscle-invasive bladder cancer and muscle-invasive bladder cancer of different stages. Clustering analysis revealed that most cell lines were basal. Non-silent point mutations were also called from RNAseq data. The investigators then performed a drug screen with 1,707 chemical substances identified from various drug libraries on 23 bladder cancer cell lines. The chosen cell lines included different subtypes, mutational landscapes, sensitivity or resistance to cisplatin, and adequate proliferation rates. In this screen, 471 molecules were found to have inhibitory effects on bladder cancer cells, including approved anticancer drugs. In addition, numerous drugs used for other conditions, such as malaria, hypercholesterolemia, and psychiatric disorders, exhibited antineoplastic effects that inhibited bladder cancer cell lines. Researchers were able to identify molecular targets or mechanisms of action for 48% of screened drugs. Among these, 28% were kinase inhibitors, and 11% were histone deacetylase inhibitors. In general, cell lines classified as luminal had lower sensitivity to treatment than basal cell lines.
Ertl et al. then focused on Clofarabine, a purine analogue and antimetabolite that was initially developed for hematologic malignancies. Clofarabine had inhibitory effects on bladder cancer cell lines at micromolar concentrations. The combination of Clofarabine with cisplatin or a histone deacetylase inhibitor (romidepsin) led to a more significant decrease in cell viability than monotherapy with each agent. Clofarabine also showed similar anticancer effects in vivo. All clofarabine-treated mice showed complete remission in a mouse xenograft model using the patient-derived VUC48 bladder cancer cell line. When the xenografts were allowed to develop for 16 days before treatment, complete remission was still observed in all treated mice. In a xenograft model of the highly aggressive sarcomatoid carcinoma (SaC) bladder cancer variant, clofarabine treatment led to partial or complete remission in most animals. After a 16-day treatment pause, Clofarabine re-challenge for 10 days led to complete remission in all animals.
The study by Ertl et al. provides innovative and valuable insights into the repurposing of existing drugs as a potential strategy to identify effective agents for treating patients with bladder cancer.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine, New York City, New York
References:
- Ertl IE, Lemberger U, Ilijazi D, et al. Molecular and Pharmacological Bladder Cancer Therapy Screening: Discovery of Clofarabine as a Highly Active Compound [published online ahead of print, 2022 Apr 4]. Eur Urol. 2022;S0302-2838(22)01678-5. doi:10.1016/j.eururo.2022.03.009