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Published on: September 12, 2019
Preclinical 3D model screening reveals digoxin as an effective therapy for a rare and aggressive type of endometrial
Pooja Praveen Kumar1, DuPreez Smith1, James Key2
1Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada.
Objective:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Dedifferentiated endometrial carcinoma (DDEC) is aggressive and lacks treatments. This study found digoxin effectively suppressed DDEC tumor growth in preclinical models, offering a potential new therapy for SWI/SNF-inactivated cancers.
Area of Science:
- Oncology
- Cancer Therapeutics
- Molecular Oncology
Background:
- Dedifferentiated endometrial carcinoma (DDEC) with SWI/SNF complex inactivation is aggressive and lacks effective systemic therapies.
- Developing targeted preclinical models is crucial for advancing therapeutic strategies against rare and aggressive cancers.
Purpose of the Study:
- To establish patient tumor-derived 3D spheroid models for dedifferentiated endometrial carcinoma (DDEC).
- To identify potential systemic therapies for SWI/SNF-inactivated DDEC through drug repurposing screens.
Main Methods:
- High-throughput drug repurposing screens were conducted on 3D spheroid models of DDEC cell lines with specific SWI/SNF inactivations (SMARCA4 and ARID1A/ARID1B).
- In vitro dose-response analyses and in vivo xenograft models were used to evaluate candidate drugs, including digoxin and digitoxin.
Main Results:
- Cardiac glycosides, digoxin and digitoxin, were identified as candidate drugs in DDEC 3D models.
- Digoxin and digitoxin demonstrated inhibitory activity with lower IC50 values in DDEC cells compared to non-DDEC endometrial cancer cells.
- Digoxin significantly suppressed DDEC tumor growth in vivo at clinically relevant concentrations.
Conclusions:
- Patient-derived 3D spheroid models of DDEC enabled the identification of digoxin as a potent suppressor of tumor growth.
- Digoxin shows promise as a systemic therapy for SWI/SNF-inactivated DDEC.
- These findings may extend to other SWI/SNF-inactivated tumor types, highlighting digoxin's therapeutic potential.
