Poster Presentation 38th Lorne Cancer Conference 2026

Repurposing the cardiac glycoside digoxin as a targeted treatment for SMARCA4-mutant ovarian cancer (#147)

Natisha R Field 1 , Kristie-Ann Dickson 1 , Tao Xie 1 , Amy Sarker 1 , Najah T Nassif 1 , Alen Faiz 1 , Deborah J Marsh 1
  1. University of Technology Sydney, Ultimo, NSW, Australia

Background: SMARCA4, encoding one of two catalytic subunits of the SWI/SNF chromatin remodelling complex, is mutated in 5-7% of cancers, with a particular prevalence in treatment-resistant and poorly differentiated tumour variants [1-3]. Among these is small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), a rare and aggressive ovarian cancer driven by inactivating SMARCA4 mutations [4]. A promising treatment approach for SCCOHT and other SMARCA4-mutant cancers is to identify therapeutics which may selectively target vulnerabilities created by SMARCA4 loss.

 

Objectives: To use the Cancer Dependency Map (DepMap) (https://depmap.org/portal/) to identify compounds predicted to selectively inhibit SMARCA4-mutant cancers and validate the top candidate in a panel of ovarian cell lines including SCCOHT.

 

Methods: The PRISM repurposing 19Q4 dataset contains cell viability data from 578 cell lines treated with 4518 compounds. The status of SMARCA4 alterations in these cell lines was assessed using mutational and copy number data from DepMap. Unpaired t-tests corrected for false discovery were used to identify compounds showing significant inhibitory differences between SMARCA4-mutant and wild-type groups (adjusted p<0.05). The top candidate was investigated in an ovarian panel containing  four SMARCA4-mutant cancer cell lines (three SCCOHT and one dedifferentiated), five SMARCA4-wild-type cancer cell lines, and one immortalised fallopian tube epithelial cell line using functional assays including 2D and 3D-bioprinted cell viability (MTS, CellTiter-Glo), proliferation (live-cell imaging) and survival (colony formation).

 

Results and conclusions: The pan-cancer analysis identified K-Strophanthidin as the top predicted candidate (adjusted p=0.00385). K-Strophanthidin was investigated previously for cardiovascular disease but replaced by digoxin, another cardiac glycoside with superior bioavailability. Digoxin was approved by the FDA in 1954 and TGA in 1991 to treat heart failure. Existing preclinical studies support the repurposing of digoxin as an anticancer agent across multiple cancer types [5-8]; however, to date, no links have been drawn between SMARCA4 mutational status and digoxin. Our in vitro validation has confirmed SMARCA4-mutant ovarian cancer cells display a remarkable sensitivity to K-Strophanthidin and digoxin, marked by a significant inhibition of viability, proliferation and survival. Work is underway to investigate mechanisms driving this sensitivity. These results position digoxin as a potential therapy to target SMARCA4-mutant cancer, including SCCOHT.

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