Preclinical study explores approved drug for ovarian cancer

An iron-binding drug that is already approved for the treatment of other diseases could provide a novel way to attack ovarian tumours, new research has shown.

Iron is essential for multiple cellular processes, so actively multiplying cancer cells often need larger amounts of it than normal cells. That’s especially true in ovarian cancers.

The preclinical study, led by Weill Cornell Medicine researchers, looked at the iron-binding drug deferiprone and combined the analysis of human ovarian tumours and animal models of the disease. Iron-chelating drugs bind tightly to iron, preventing cells from using it.

“We thought that was a perfect opportunity to try a new approach, because deferiprone has been successfully used for other diseases with abnormal iron accumulation,” said senior author Dr Juan Cubillos-Ruiz, distinguished associate professor for infection and immunology in obstetrics and gynaecology at Weill Cornell Medicine.

To confirm the importance of iron in ovarian cancer, Dr Cubillos-Ruiz’s team first looked at a collection of human tumour samples they have amassed over the past decade and analysed public genomic datasets from ovarian cancer patients.

“We can isolate different components of tumours from ovarian cancer patients, and study their molecular processes,” Cubillos-Ruiz explained.

The scientists found that ovarian cancer cells demonstrate increased expression of iron-related genes, which correlated with poor patient prognosis. The investigators also found that fluid surrounding ovarian tumours contain high iron content that is readily available to cancer cells.

The researchers next looked at animal models of the disease.

“We have advanced mouse models of metastatic ovarian cancer that are immunocompetent, so this allows us to study the immune system response in the disease, which is a crucial component,” Dr Cubillos-Ruiz said.

Previous iron-related studies have used mice with compromised immune systems, precluding the understanding of how different therapies affect immune responses to tumours.

The investigators found that the mice recapitulated the disease features quite well: as ovarian cancer progressed, there was more iron accumulation in the tumour, and the cancer cells selectively over-expressed the iron-related gene signatures.

In the animals, deferiprone treatment worked even better than cisplatin, the current standard for ovarian cancer chemotherapy, and functioned directly inside the cells.

“We demonstrated that deferiprone can chelate iron in ovarian cancer cells, in vivo” said lead author Dr Tito Sandoval, a former postdoctoral fellow in Dr Cubillos-Ruiz’s lab.

“We found that combining cisplatin and deferiprone markedly extended the survival of mice with metastatic ovarian cancer, working synergistically compared with the monotherapies. So, we decided to identify the mechanisms behind this effect.”

The team found that by starving cancer cells of iron, deferiprone triggers a cellular stress response, which prompts the immune system to attack them. Cisplatin affects cancer cell DNA replication, so the two drugs appear to be complementary.

Dr Cubillos-Ruiz is now working with clinical collaborators to design human trials of the new approach.

Though deferiprone is already approved for treating other conditions, he emphasised that the team still needs to determine the best way to use it against ovarian cancer.

“We want to maximise the potential therapeutic effects, so the clinical trial design is critical,” he added.