Iron-binding drug could be used to treat ovarian cancer

An iron-binding drug that is already approved for treatment of other diseases could provide a novel way to attack ovarian tumours. That’s according to a preclinical study — led by Weill Cornell Medicine researchers and published in the journal Cancer Discovery — which combined the analysis of human ovarian tumours and animal models of the disease.

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.

“We thought that was a perfect opportunity to try a new approach, because there is an FDA-approved iron-chelating drug called deferiprone that has been successfully used for other diseases with abnormal iron accumulation,” said senior author Dr Juan Cubillos-Ruiz, from Weill Cornell Medicine. Iron-chelating drugs bind tightly to iron, preventing cells from using it.

To confirm the importance of iron in ovarian cancer, Cubillos-Ruiz’s team first looked at a collection of human tumour samples they’ve amassed over the past decade and analysed public genomic datasets from ovarian cancer patients with the help of an international team of collaborators. Cubillos-Ruiz explained, “We can isolate different components of tumours from ovarian cancer patients, and study their molecular processes.”

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

The investigators next looked at animal models of the disease, with Cubillos-Ruiz noting, “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.” 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 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.

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, 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,” Cubillos-Ruiz said.

Image credit: iStock.com/Lars Neumann