A team of international researchers has identified a key pathway in some aggressive ovarian tumours that could be targeted with medications currently used to treat type 2 diabetes.
The study, led by Dr Andrew Stephens from Prince Henry’s Institute (PHI) in Australia, has for the first time demonstrated the activity of an enzyme within a subset of ovarian tumours that suppresses an otherwise normal infection-fighting immune response.
These ovarian tumours, known as high-grade, serous epithelial ovarian carcinomas (HGSOC), account for between 80 and 95% of ovarian tumours diagnosed, and remain the fourth-highest cause of cancer-related death for women.
Previous studies into links between cancer and immunity have shown that a protein called CXCL10, which stimulates the immune system, is produced in high levels in the presence of some types of tumours. This molecule is part of an early immune response normally switched on to attack an invading tumour.
“Under normal circumstances, CXCL10 recruits white blood cells to come in and fix the problem,” said Dr Stephens. “But the paradox is that in ovarian tumours, we weren’t seeing a corresponding influx of white blood cells.”
The latest study identified the reason; the culprit being an enzyme that is produced by the HGSOCs to modify CXCL10 and inhibit its function.
“Ultimately, we identified that this protein (CXCL10) was being modified by an enzyme that was also being produced in the tumour, and what that enzyme does is switches off the CXCL10,” said Dr Stephens.
“So instead of promoting the recruitment of immune cells, the tumour seems to have hijacked that response and turned it off at an early stage of tumour progression.”
The finding means that existing type 2 diabetes medications (DPP-4 inhibitors), designed for the same modifying enzyme, could be used to inhibit its activity and allow CXCL10 to do its job.
Clare Scott, Medical Oncologist and Laboratory Head at Walter and Eliza Hall Institute, said that the study was an exciting step forward in the field of immune therapy for ovarian cancer.
“Understanding the way in which the immune system is switched off in ovarian cancer is a new discovery which points the way forward for further research,” said Scott, who wasn’t involved in the study.
“But the diabetes drug may or may not be the best way to deal with this - it is a bit early to say,” she added.
Because the proposed drugs may need to be given earlier in high-grade cancers to be effective, developing a test to identify dangerous ovarian cancers at an early stage is needed, she said.
She said such cancers behave differently to low-grade tumours, so the next step was to develop a test to determine which ovarian cancers switch off the immune response.
Dr Stephens agreed the research was still in its early days.
“We need to test whether using this enzyme to block the process will restore immune function. That’s the next study we do. That will be an animal study and if that’s successful, we’ll move onto human trials,” he said.
“I’m hopeful in conjunction with existing chemotherapy, this might provide a bit of a boost by getting the patient’s own immune system to attack the tumour and at least slow any further progression. Ideally, this might even help to regress tumours - or perhaps prevent them from forming in the first place.”
The study, published in the International Journal of Cancer, was conducted in collaboration with Monash Health, Hasanuddin University in Indonesia and Lincoln Research Centre in Christchurch.