New Cardio-Oncology Drug Aims To Protect The Heart While Increasing Effectiveness Of Cancer Treatments

First-of-its-kind drug shown to work safely in mice and human cells.

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.

Sutendra points out that this stress response likely evolved to benefit the heart in the face of acute threats, because it allows the heart to prioritize energy conservation and damage repair. But when the stressor becomes chronic, as in the case of cancer treatment, it starts shutting down the heart.

“Then it becomes an adverse event that promotes cell death, and we want to stop it at that point,” Sutendra says.

The team identified the protein ZNF281 as a transcription factor that allows for the expression of certain genes and shows up in the heart when it’s under stress. It increases the expression of an enzyme called TRIM35 that is implicated in heart failure.

To confirm this, they overexpressed the factor in mice and found those mice developed cardiac dysfunction. Then they tested the opposite effect by making mouse models that could not generate the protein. When those mice were treated with anthracycline, their hearts stayed normal.

The team also identified that although ZNF281 is involved in cell death in the heart, it promotes cell growth in cancer tumours. It behaves differently because the heart is an oxygen-rich environment, whereas tumours are oxygen-poor.

“The idea came to us that perhaps we can target proteins that are tagged by oxygen that do one kind of signalling in the heart and different signalling in the tumour,” Sutendra says.

Targeted drug development
Transcription factors are notoriously difficult to target with drugs, but the team worked with medicinal chemist Amir Tabatabaei Dakhili, assistant professor in the Faculty of Pharmacy and Pharmaceutical Sciences, to generate a small molecule that could prevent it from binding with DNA.

“Our medicinal chemist was able to find a pocket that was revealed when ZNF281 was binding with the DNA, so he developed a drug that can bind in that pocket and disrupt it from binding with DNA,” Sutendra explains.

The next step for the team will be to test for effectiveness and side-effects in other animal models before Health Canada will allow them to proceed to clinical trials. They will also test the drug against a broader spectrum of tumour types, accompanied with various cancer treatments.

They will also explore whether their findings could be relevant in other forms of heart failure, and even in other diseases.

“It’s really a team effort,” says Sutendra. “We have a lot of spectacular researchers here who are willing to work together and collaborate on big projects like this. If you have the dedication, you can make these discoveries and make them work.”

This study was carried out with grants from the Canadian Institutes of Health Research and in collaboration with members of several departments across the university, including prostate cancer surgeon Adam Kinnaird, Canada Research Chair in Applied Molecular and Mitochondrial Medicine Evangelos Michelakis, Canada Research Chair in Pharmacotherapy of Energy Metabolism in Obesity John Ussher, and pharmacist Seyed Amirhossein Tabatabaei-Dakhili, as well as researchers from Duke University.