New research uncovering a vulnerability in prostate cancer cells could provide ways to improve treatments for prostate cancer. 

A major international study, led by scientists from Flinders University in Australia and South China University of Technology, revealed that two enzymes, PDIA1 and PDIA5, play a crucial role in helping prostate cancer cells grow, survive and resist treatment. These enzymes act as molecular bodyguards for the androgen receptor (AR), a protein that fuels prostate cancer. When PDIA1 and PDIA5 are blocked, the AR becomes unstable and breaks down, leading to cancer cell death and tumour shrinkage in both lab-grown cells and animal models. 

The research, published in the journal Proceedings of the National Academy of Sciences (PNAS), also found that combining drugs that block PDIA1 and PDIA5 with enzalutamide, a widely used prostate cancer medication, significantly boosted the treatment’s effectiveness. 

“We’ve discovered a previously unknown mechanism that prostate cancer cells use to protect the androgen receptor, which is a key driver of the disease,” said senior aAuthor and Professor Luke Selth, Head of Prostate Cancer Research and Co-Director of Flinders Health and Medical Research Institute’s Cancer Impact programme. “By targeting these enzymes, we can destabilise the AR and make tumours more vulnerable to existing therapies like enzalutamide.” 

Professor Jianling Xie, who led the study, said that this combination therapy worked well in patient-derived tumour samples and in mice, suggesting strong potential for future clinical trials. 

“This is an exciting step forward,” said Xie. “Our findings show that PDIA1 and PDIA5 are not just helpers of cancer growth but they’re also promising targets for new treatments that could work alongside existing drugs.” 

Future studies needed to make drugs safe for use

The study also found that PDIA1 and PDIA5 help cancer cells manage stress and maintain energy production. Blocking them causes damage to the cells’ mitochondria, the parts of the cell that generate energy, and leads to oxidative stress, which further weakens the cancer. 

“This dual impact of hitting both the AR and the cancer’s energy supply makes these enzymes especially attractive targets,” Xie added. “It’s like cutting off both the fuel and the engine at the same time.” 

Selth suggested that, while current drugs blocking PDIA1 and PDIA5 show promise, more work is needed to make them safe and effective for use in patients. Some of the existing compounds may affect healthy cells, so future studies will focus on developing safer inhibitors. 

Prostate cancer is the second most common cancer in men worldwide. Although treatments like hormone therapy and AR-targeting drugs have helped many patients, resistance to these therapies is a major challenge. This new discovery could help overcome that hurdle and improve outcomes for men with advanced prostate cancer. 

Bruno Quinney, Content Team, DDW