Abstract C041: Drug repurposing to target TGF-β in chemoresistant high-grade serous ovarian cancer

Abstract

Abstract High-grade serous ovarian cancer (HGSOC) has low 5-year survival rate of 48%, due to chemotherapy resistance. Effective new therapies are required to improve the survival rate of HGSOC. TGF-β is a family of proteins associated with epithelial-mesenchymal transition and have been implicated in ovarian cancer progression and chemoresistance. Drugs that target TGF-β may have potential to be used to treat chemoresistant HGSOC and control tumour growth and progression. Drug repurposing is a strategy to identify new uses for approved drugs outside of their original indication, and ensure timely access to efficacious and cost-effective therapy for chemoresistant HGSOC. The aims of the study is to determine the effect of the repurposed drug teniposide on HGSOC cell growth, death, and apoptosis. A ligand-based screening was performed by Cresset Discovery for approved drugs that bind to the TGF-β receptor complex and ligand. Teniposide was shortlisted according to its dosing, lipid solubility, pharmacokinetics, and side effects. MTT assays were performed on eight molecularly-characterised HGSOC cell lines to obtain the IC50 of teniposide. The effect of the IC50 dose of teniposide on HGSOC cell growth, death, and apoptosis were monitored on the IncuCyte live-cell imager. Western blotting was performed to determine the expression of TGF-β signalling pathway proteins after treatment with teniposide. The average IC50 of teniposide in HGSOC cell lines is 10µM, within the range of the maximum plasma concentration (61µM). HGSOC cell lines treated with 10µM teniposide showed decreased cell growth, and increased cell death and apoptosis, similar to HGSOC cell lines treated with clinically-relevant dose of carboplatin (30µM). HGSOC cell lines treated with 10µM teniposide showed significantly higher cell death and apoptosis compared to treatment with 30µM carboplatin. Our preliminary results show that teniposide significantly reduced proliferation of HGSOC and has potential to be repurposed for treatment of chemoresistant HGSOC. Citation Format: Michelle WY Wong-Brown, Zlata Johnson, Saad Salem, Bayley G Matthews, Caroline E Ford, Deborah J Marsh, Nikola A Bowden. Drug repurposing to target TGF-β in chemoresistant high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C041.