A team of University of Alberta researchers has developed a cardio-oncology drug that protects the heart from chemotherapy damage while enhancing the effectiveness of cancer treatments against tumour growth and spread.
In a paper published today as the cover story in Science Translational Medicine, the team identifies the target protein ZNF281 and a new drug they've developed called ZIM, or ZNF281 Interfering Molecule.
They demonstrate that, by treating mice with lung cancer with the new drug in addition to a common cancer drug, anthracycline, they protected the heart against chemo-induced failure, enhanced tumour regression and prevented cancer from metastasizing, or spreading to other areas of the body.
"We found our drug was able to prevent the actions of the ZNF281 protein," explains principal investigator Gopinath Sutendra, associate professor and co-associate chair of research for the Department of Medicine in the Faculty of Medicine & Dentistry, Canada Research Chair in Cardio-Oncology and Molecular Medicine, and Alberta Innovates Translational Health Chair in Cardio-oncology.
"We saw complete protection of the heart and we saw even better regression with the tumours. A few mice even had complete regression of their cancer within the timeline that we treated them," says Sutendra.
The primary tumours in the ZIM-treated mice decreased significantly, and there was no spread of the tumours to other parts of the body. The team found similar results when they tested the drug on mice with melanoma, the most dangerous form of skin cancer.
They also found the ZNF281 protein was induced in human heart cells taken from patients who had developed cardiotoxicity - heart failure caused by chemo - suggesting the drug could have a similar protective effect in patients.
"We saw our entire signalling pathway was present in human myocardial samples, suggesting that this therapy could be quite effective and translational to patients," explains Sutendra.
A process of discovery
Today's paper is the culmination of seven years of work in the Sutendra lab to uncover why chemotherapies and other cancer treatments often damage the heart, causing a condition called dilated cardiomyopathy, in which the ventricle walls are damaged.
"We speculated that perhaps all these different classes of chemotherapeutics, which appear to target a relatively select and distinct pathway in the tumour, may all induce a similar stress-sensing pathway in the heart, resulting in chemo-induced cardiomyopathy," the researchers explain in their paper.
They discovered that the heart's integrated stress response system - which usually kicks in when the body is faced with low oxygen, nutrient deprivation or iron deficiency - is also triggered by numerous DNA-damaging cancer treatments.
