Poster Presentation NSW State Cancer Conference 2023

Repurposing teniposide to target TGF-β in chemoresistant high-grade serous ovarian cancer (#303)

Zlata Johnson 1 2 3 , Saad Salem 1 2 3 , Bayley G Matthews 1 2 3 , Caroline E Ford 4 5 , Deborah J Marsh 5 6 , Nikola A Bowden 1 2 3 , Michelle WY Brown 1 2 3
  1. Centre for Drug Repurposing and Medicines Research, Hunter Medical Research Institute, New Lambton Heights, NSW , Australia
  2. NSW Regional Cancer Research Network, Newcastle, NSW, Australia
  3. University of Newcastle, New Lambton Heights, NEW SOUTH WALES, Australia
  4. Gynaecological Cancer Research Group, University of New South Wales, Sydney, NSW, Australia
  5. SPHERE Cancer Clinical Academic Group, Sydney, NSW , Australia
  6. Translational Oncology Group, University of Technology Sydney, Sydney, NSW, Australia

Background

High grade serous ovarian cancer (HGSOC) has a 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, angiogenesis, and proliferation, and have been implicated in ovarian cancer progression and chemoresistance. Drugs that target TGF-β signalling may potentially 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 ensuring timely access to efficacious and cost-effective therapy for chemoresistant HGSOC.

  

Aim

To determine the effect of the repurposed drug teniposide on HGSOC cell growth, death, and apoptosis.

 

Methods

A ligand-based screening was performed by Cresset Discovery for approved drugs that bind to the TGF-β receptors . Teniposide, an antineoplastic agent, was shortlisted due to its favourable 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.

 

Results

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.

 

Discussion and Conclusion

Our preliminary results show that teniposide significantly reduced proliferation of HGSOC and has potential to be repurposed for treatment of chemoresistant HGSOC.