Poster Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Repurposing hypertension medications for endometrial cancer treatment. (#422)

Tess L Symington 1 2 , Joshua J Fisher 3 4 , Paul Tooney 1 5 , Kirsty G Pringle 1 2
  1. School of Biomedical Science and Pharmacy, University of Newcastle, Newcastle, NSW, Australia
  2. Womens Health Research Program, Hunter Medical Research Institute, Newcastle, Australia
  3. School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia
  4. Mothers and Babies Research Program, Hunter Medical Research Institute, Newcastle, NSW, Australia
  5. Drug Repurposing and Medicines Research Program, Hunter Medical Research Institute, Newcastle, Australia

Endometrial cancer is the fifth most diagnosed cancer in females, with the incidence rates predicted to increase by 50% by 2040. Despite these rising rates, only five drugs have been approved for treatment by the Federal Drug Administration. Previous work has highlighted the potential of anti-hypertensive medications that antagonise the renin-angiotensin system to be repurposed for endometrial cancer treatment. This project aimed to characterise the expression of renin-angiotensin system components in endometrial cancer and to explore the potential of repurposing renin-angiotensin system antagonists for endometrial cancer treatment.

RNAseq data from The Cancer Genome Atlas PanCancer Atlas Uterine Corpus Endometrial Carcinoma study was used to explore the expression of renin-angiotensin system genes in endometrial cancer and determine their association with patient survival. The primary screen from the Broad Institute’s Drug Repurposing HUB was used to investigate the effect of renin-angiotensin system antagonists (n=37) on the viability of endometrial cancer cell lines in vitro (n=22).

High expression of angiotensinogen, a protein essential for renin-angiotensin system signalling, was associated with lower progression free (HR: 1.66 (CI:1.13-2.43), p = 0.01) and overall survival (HR: 1.86 (CI:1.17-2.95), p = 0.009) in endometrial cancer patients. Similarly, high expression of the angiotensin II type I receptor, a driver of angiogenesis and cellular proliferation, was associated with lower overall survival (HR: 2.16 (CI:1.33-3.496), p < 0.002) of endometrial cancer patients. Angiotensin II type I receptor antagonists showed the strongest potential for treatment, with azilsartan, eprosartan, and candesartan causing a consistent decrease in cell viability across 22 different endometrial cancer cell lines.

This study highlights the importance of both angiotensinogen and the angiotensin II type I receptor in endometrial cancer progression. Of note, angiotensin II type I receptor antagonists consistently reduced cell viability, emphasising the potential to repurpose these drugs as therapeutic options to treat endometrial cancer.