Clofazimine, an antibiotic long used for treating leprosy and tuberculosis, may be repurposed as a promising potential treatment for triple-negative breast cancer, a study in mice suggests.
The treatment targets the Wnt signaling pathway – key in triple-negative breast and other cancer types – preventing cells from growing, and can be safely combined with conventional chemotherapeutic agents that kill the cells, researchers found.
The study, “Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor,” was published in the journal Cancer Letters.
The best way to treat cancer is by using therapies that specifically target cellular elements that promote survival of cancer cells without affecting the healthy ones.
“These elements – called oncogenes – are necessary to transform healthy cells into malignant cells, so it is important to bring them down without damaging neighboring cells,” Vladimir Katanaev, PhD, professor at the University of Geneva and senior author of the study, said in a press release.
Triple-negative breast cancer got its name because these tumors don’t produce any of the three hormone receptors that are common in breast cancer: progesterone receptor, estrogen receptor, or HER2. In other breast cancer types, these receptors can be therapeutically targeted to treat patients.
TNBC, less well-understood, is often driven by multiple interconnecting mutations and molecular pathways that make it more difficult to treat.
The Wnt signaling pathway – a group of proteins that mediates the communication between cells, which takes place through chemical signals or signaling pathways – plays an essential role during fetal development, as it allows cells to divide and migrate. While this pathway is largely deactivated in adults, some cancers, like triple-negative breast cancer, reactivate it to grow and form metastasis.
Researchers have been working on approaches that target this pathway for some time. But due to Wnt’s role in normal tissue renewal and regeneration — it stays “on” in stem cells and non-specialized cells, which work to repair tissue damage — none of the therapies developed to date have been found safe to use. But clofazimine, an approved oral antibiotic used for leprosy and tuberculosis, is different.
In a prior report, investigators at the Universities of Geneva and Lausanne, in Switzerland, discovered that clofazimine also worked as an inhibitor in the Wnt signaling pathway. Due to its exceptional safety profile, they now sought to explore the compound’s anti-cancer activity in triple-negative breast cancer preclinical models, to determine if it could be repurposed for cancer treatment.
Since approved medicines are already known to be safe in humans, repurposed compounds usually can skip Phase 1 clinical testing and go straight to Phase 2 and Phase 3 trials to determine their effectiveness against other diseases. In theory, these agents should enter the market faster than newly developed compounds.
The team tested the antibiotic in lab-grown cells and in mice transplanted with cells from triple-negative breast cancer patients. They found that clofazimine effectively stopped the progression of triple-negative breast cancer by specifically targeting the Wnt pathway.
“With clofazimine, tumor growth is significantly reduced. In addition, we did not detect any adverse side effects, an essential aspect of the drug development process,” Katanaev said.
Investigators also found that clofazimine could be safely combined with doxorubicin, a conventional chemotherapy, with the combination showing better anti-cancer effects than any agent alone.
“Clofazimine acts as an inhibitor of the Wnt signaling pathway: the sick cell can no longer divide but does not die. Doxorubicin, on the other hand, kills cells that have stopped growing. A combination of great efficacy!” said Alexey Koval, the study’s co-first author.
These results suggest that clofazimine is “a highly promising targeted drug against [triple-negative breast cancer] and other Wnt-dependent tumors,” the researchers said. And it’s a potential therapy with “decades of application” showing only “acceptable moderate side effects,” they added.
“The novel mechanism of action of the drug and its additivity with conventional chemotherapy permits initiation of repositioning clinical trials,” the researchers concluded. “In case of success, this work will bring about the first targeted therapy against the deadliest form of breast cancer.”
We are sorry that this post was not useful for you!
Let us improve this post!
Tell us how we can improve this post?