Treating a Mutation Tames The ‘Red Devil’ Chemotherapy Drug
Harmful side effects from the common chemotherapy drug doxorubicin could be caused by a single mutation, according to a study published in Cell Stem Cell.
The cardiotoxic effects of the chemotherapy drug doxorubicin – an infamous drug nicknamed the ‘Red Devil’ because of its bright red colour and side effects – could be prevented in patients with the mutation by treating them with retinoic acid, according to Paul Burridge, PhD, assistant professor of Pharmacology and senior author of the study.
“In the future patients could be given CD1530, or a similar drug, and this would reduce their chances of experiencing cardiotoxicity,” said Prof Burridge.
Doxorubicin is the most common chemotherapy drug and is mostly used in children and in breast cancer. However, patients receiving doxorubicin experience dose-dependent cardiotoxicity; up to 10% of childhood cancer survivors will develop heart failure in the 30 years after their treatment.
A previous study showed that people who experience cardiotoxicity from chemotherapy were more likely to have a genetic variation called a single nucleotide polymorphism (SNP) in a gene called retinoic acid receptor gamma (RARG).
In this study, Dr Burridge and colleagues created patient-derived heart cells with this SNP and administered doxorubicin, finding that those cells indeed were more sensitive to the treatment. After correcting the mutation using genetic editing tools, the additional toxicity disappeared.
“This confirmed to us that RARG is important in doxorubicin cardiotoxicity sensitivity,” Prof Burridge said.
The researchers tried several drugs that could block the downstream effects of this mutation, finding that one drug, CD1530, made cardiomyocytes less sensitive to the chemotherapy. The drug activates retinoic acid receptors that are usually left inactivated in patients with the SNP, preventing activation of a cardio-protective pathway that is ill-suited for chemotherapy.
The investigators hope to test this drug in human patients, thanks to their use of human cells.
“Because all of our data was generated in human cells, there isn’t a need for a second basic research step,” Prof Burridge said. “We believe we will be able to begin the first stages of a clinical trial, testing the safety of RARG agonists and how effective they are in patients.”
Source: Northwestern University
