Cardiotoxic effects of common chemotherapy drugs could be avoided

Harmful side effects of a common chemotherapy drug could be the result of a single mutation, according to a study published in Stem cell.

The cardiotoxic effects of the chemotherapeutic drug doxorubicin could be avoided in patients with the mutation by treating them with retinoic acid, according to Paul Burridge, PhD, assistant professor of pharmacology and lead author of the study.

“In the future, patients may be given CD1530 or a similar drug, which would reduce their risk of cardiotoxicity,” said Burridge, who is also a member of the Robert H. Lurie Comprehensive Cancer Center at Northwestern University.

Doxorubicin is the most common chemotherapy drug, mainly used in children and in breast cancer. However, patients taking doxorubicin exhibit dose-dependent cardiotoxicity; up to 10 percent of childhood cancer survivors will develop heart failure within 30 years of treatment.

A previous study by collaborators at the University of British Columbia, Vancouver, showed that people with cardiotoxicity following chemotherapy were more likely to have a genetic variation called single nucleotide polymorphism (SNP ) in a gene called the gamma retinoic acid receptor (RARG).

In the current study, Burridge and colleagues created heart cells derived from patients with this SNP and treated them with doxorubicin, finding that these cells were indeed more sensitive to treatment. Moreover, when they corrected the mutation using gene editing tools, the additional toxicity disappeared.

“This confirmed to us that RARG is important in susceptibility to doxorubicin cardiotoxicity, ”said Burridge.

Investigators tested several drugs that could reverse the downstream effects of this mutation, finding that a drug – called CD1530 – made cardiomyocytes less sensitive to chemotherapy. The drug works by activating retinoic acid receptors which are usually left inactivated in patients with PNS, preventing activation of a cardioprotective pathway poorly suited to chemotherapy.

Burridge said this study illustrates the utility of pre-chemotherapy genetic screening and shows how precision medicine can be a powerful tool in chemotherapy. Next, the researchers hope to test this drug in human patients.

“Because all of our data was generated in human cells, there is no need for a second step of basic research,” Burridge said. “We believe we will be able to begin the early stages of a clinical trial, testing the safety of RARG agonists and their efficacy in patients.”