Researchers at the University of Alberta Faculty of Medicine and Dentistry have found a way to increase chemotherapy's effectiveness while shielding the heart from its harmful side effects.
Many chemotherapeutic drugs, including anthracyclines such as doxorubicin, are known to cause damage to the heart as a result of the activation of p53. This protein fights cancer by inducing apoptosis—programmed cell death—in tumors. However, it also induces apoptosis in other organs, including the heart, where it promotes cardiac failure.
Inhibiting p53 has demonstrated efficacy in preclinical models of heart failure, but since p53 is important to antitumor activity, inhibiting it would not be of use in treating or preventing chemotherapy-induced cardiotoxicity. For this reason, the researchers at the University of Alberta sought a p53-targeting therapy that would decrease chemotherapy-induced apoptosis in the myocardium while simultaneously increasing apoptosis in the tumor.
Previous studies have found that the tetrameric form of pyruvate kinase muscle 2 (PKM2), which directly interacts with p53, is preferentially oxidized in the heart and inhibits apoptosis there, yet this very same substance increases p53 activity in low oxidation environments such as tumors.
For their study, published in Science Translational Medicine, the University of Alberta investigators identified a compound called TEPP-46 that stabilizes tetrameric PKM2 so that it protects cardiomyocytes—cardiac muscle cells—while simultaneously enhancing anthracyclines' ability to kill cancer cells. In animal models of lung cancer, treatment with TEPP-46 inhibited cardiomyocyte apoptosis induced by doxorubicin and prevented cardiac dysfunction. At the same time, it boosted cancer cell apoptosis and tumor regression.
"At the clinical level, we've known for some time that heart dysfunction from chemotherapy is a major issue, but at the scientific level, we've only recently begun to look at signaling pathways that may be implicated in this condition," commented Gopinath Sutendra, PhD, Alberta Innovates Translational Health Chair in Cardio-Oncology at the University of Alberta. "This is the first targeted therapy at the preclinical level to actually prevent the side-effects of chemotherapy on the heart and simultaneously enhance tumor regression."
The researchers hope that drugs similar to TEPP-46 will soon be tested in clinical trials. "The beauty of our work is that many of these drugs are already being tried in early-phase clinical trials for other diseases," remarked Dr. 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."
Bruno Saleme, the study's first author and a recent recipient of the Alberta Innovates Graduate Scholarship, noted that these findings could be applicable to fields beyond cancer research: "We also believe the implications of our work may extend to other forms of heart failure as well."
For More Information
Saleme B, Gurtu V, Zhang Y, et al (2019). Tissue-specific regulation of p53 by PKM2 is redox dependent and provides a therapeutic target for anthracycline-induced cardiotoxicity. Sci Transl Med, 11(478):eaau8866. DOI:10.1126/scitranslmed.aau8866
Image credit: Jordan Carson