Discovery boosts chemo while protecting heart

University of Alberta medical research may bolster chemotherapy potency while protecting heart from side-effects

15 September 2019

Original Story: Edmonton Journal

Researchers have long known that the aggressive attack on cancer cells from chemotherapy often causes damage to other cells in the body. When the damage affects the heart, patients can be more prone to develop heart problems years down the road.

This inspired Gopinath Sutendra, University of Alberta professor and Alberta Innovates cardio-oncology translational health chair, to research possible solutions.

"This is the first targeted therapy at the preclinical level to actually prevent the side-effects of chemotherapy on the heart and simultaneously enhance tumour regression," Sutendra said.

Chemotherapy is especially problematic for the heart because cells there regenerate more slowly than in other organs, Sutendra said, making damage nearly irreversible.

While the heart resides in an oxygen-rich environment, a tumour resides in an oxygen-poor environment. Because it's in this oxygen-rich environment, the oxidation of proteins happens faster in the heart. Knowing this, the U of A research team-which also included Bruno Saleme, first author on the study and a recent recipient of the Alberta Innovates Graduate Scholarship-decided to target the heart.

By stabilizing a specific metabolic protein called pyruvate kinase M2 (PKM2)-also preferentially oxidized in the heart-with a drug compound, the researchers completely prevented heart damage from the chemotherapy.

"When (the protein) was tagged by oxygen in the heart, it actually preserved cardiac function when we treated the heart with chemotherapy agents," Sutendra said.

When the metabolic protein was stabilized the same way in a lung tumour, chemotherapy treatment was more effective.

The team used mice for its research, with human lung cancers and a common chemotherapy medication in pill form known to cause cardiac dysfunction in patients.

"That protein was preferentially tagged in the heart compared to the tumour where it wasn't tagged by oxygen, and this somehow changed the structure of the protein such that it was preventing the chemotherapy-mediated cardiac dysfunction in the heart," Sutendra said.

Researchers hope the findings will soon be able to be tested in clinical trials with similar drugs that stabilize the protein-pyruvate kinase M2 (PKM2)-many of which are already being tested for other diseases in clinical trials.

"We're reaching out to pharmaceutical companies that have some of these compounds that they're using in other diseases," Sutendra said. "There is interest there to test those ones in our model because then they can be moved to the clinical trial more easily."

These findings could have similar implications for other forms of heart failure, Sutendra said, which will be the next area of study for the team. The effectiveness of a similar approach in other organs of the body is another potential area of research following this discovery.

The research, published as a cover story in Science Translational Medicine, was supported by funding from the Canadian Institutes of Health Research, the Heart and Stroke Foundation and the Alberta Innovates Translational Health Chair in Cardio-oncology.