Preclinical 3D model screening reveals digoxin as an effective therapy for a rare and aggressive type of endometrial cancer

• Published in: Gynecologic oncology Vol. 188; pp. 162 - 168
• Main Authors: Kumar, Pooja Praveen, Smith, DuPreez, Key, James, Dong, He, Ganapathysamy, Ashtalakshmi, Maranda, Vincent, Wong, Nelson K.Y., Fernandez, Marta Llaurado, Kim, Hannah, Zhang, Guihua, Ewanowich, Carol, Hopkins, Laura, Freywald, Andrew, Postovit, Lynne M., Köbel, Martin, Fu, Yangxin, Vizeacoumar, Frederick S., Vizeacoumar, Franco J., Carey, Mark S., Lee, Cheng-Han
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2024
• Subjects: Animals; Cardiac glycoside; Cell Line, Tumor; Dedifferentiated cancer; Digitoxin - pharmacology; Digoxin - pharmacology; Digoxin - therapeutic use; Drug Repositioning; Drug Screening Assays, Antitumor; Endometrial Neoplasms - drug therapy; Endometrial Neoplasms - pathology; Female; High-Throughput Screening Assays; Humans; Mice; Spheroids, Cellular - drug effects; SWI/SNF; Undifferentiated cancer; Xenograft; Xenograft Model Antitumor Assays; Cardiac glycoside; Xenograft; Dedifferentiated cancer; SWI/SNF; Undifferentiated cancer
• ISSN: 0090-8258; 1095-6859; 1095-6859
• DOI: 10.1016/j.ygyno.2024.06.029

Dedifferentiated endometrial carcinoma (DDEC) characterized by SWItch/Sucrose Non-Fermentable (SWI/SNF) complex inactivation is a highly aggressive type of endometrial cancer without effective systemic therapy options. Its uncommon nature and aggressive disease trajectory pose significant challenges for therapeutic progress. To address this obstacle, we focused on developing preclinical models tailored to this tumor type and established patient tumor-derived three-dimensional (3D) spheroid models of DDEC. High-throughput drug repurposing screens were performed on in vitro 3D spheroid models of DDEC cell lines (SMARCA4-inactivated DDEC-1 and ARID1A/ARID1B co-inactivated DDEC-2). The dose-response relationships of the identified candidate drugs were evaluated in vitro, followed by in vivo evaluation using xenograft models of DDEC-1 and DDEC-2. Drug screen in 3D models identified multiple cardiac glycosides including digoxin and digitoxin as candidate drugs in both DDEC-1 and DDEC-2. Subsequent in vitro dose-response analyses confirmed the inhibitory activity of digoxin and digitoxin with both drugs showing lower IC50 in DDEC cells compared to non-DDEC endometrial cancer cells. In in vivo xenograft models, digoxin significantly suppressed the growth of DDEC tumors at clinically relevant serum concentrations. Using biologically precise preclinical models of DDEC derived from patient tumor samples, our study identified digoxin as an effective drug in suppressing DDEC tumor growth. These findings provide compelling preclinical evidence for the use of digoxin as systemic therapy for SWI/SNF-inactivated DDEC, which may also be applicable to other SWI/SNF-inactivated tumor types. •Patient-derived 3D models of dedifferentiated endometrial carcinoma (DDEC) were subjected to drug repurposing screen.•The drug screen identified digoxin as an effective anti-cancer drug in suppressing DDEC tumor growth.•DDEC displayed greater sensitivity to digoxin compared to non-DDEC endometrial cancer cells in vitro.•Digoxin significantly inhibited patient-derived DDEC tumor growth in vivo.•These results provide compelling preclinical evidence for the use of digoxin as systemic therapy for DDEC.