“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.”The heart resides in an oxygen-rich environment, compared to a tumour which resides in an oxygen-poor environment.The team found that the oxidation of proteins–a process that requires oxygen–was preferentially increased in 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 and enhanced the potency of the chemotherapy against lung tumours in preclinical mouse models.
The researchers hope the findings will soon be able to be tested in clinical trials with similar drugs that stabilize PKM2.”The beauty of our work is that many of these drugs are already being tried in early-phase clinical trials for other diseases,” said Sutendra. “We’re really happy because we think that we can push it to the next phase where hopefully patients can start seeing some of these treatments in the near future.”
“We also believe the implications of our work may extend to other forms of heart failure as well,” added Bruno Saleme, first author on the study and a recent recipient of the Alberta Innovates Graduate Scholarship.
Saleme et al. Tissue-specific regulation of p53 by PKM2 is redox dependent and provides a therapeutic target for anthracycline-induced cardiotoxicity. Science Translational Medicine, 2019; DOI: 10.1126/scitranslmed.aau8866 [Abstract]