Doxorubicin has been a mainstay in cancer treatment for more than 50 years. Sometimes called “red devil chemo,” it is potent and effective against many cancer types. But it comes with a major downside — increased risk of severe heart failure, even decades after successful cancer treatment.
Now researchers led by WashU Medicine cardiologist Ali Javaheri, MD, PhD, have identified a type of immunotherapy that prevents and treats the heart muscle damage caused by doxorubicin, based on their findings in human heart tissue, cell lines and mouse models of heart failure. The study appears in the journal Circulation.
The immunotherapy is an antibody that blocks a cell-surface protein called CD47. Several CD47 inhibitors are already in clinical trials against various cancers, making it unusual as a therapy that shows evidence of both killing cancer cells and protecting the heart. The new study suggests CD47 inhibitors could, in theory, be given in combination with doxorubicin to enhance the chemo’s anti-cancer effects while protecting the heart from the damage the chemo causes.
Long used to treat breast cancer, sarcoma, blood cancers and various pediatric cancers, doxorubicin is a standard part of the treatment regimen for an estimated 1 million cancer patients annually in the U.S. and Canada. It belongs to a class of drugs called anthracyclines, all of which increase the risk of heart failure — a complex condition with multiple triggers and feedback loops that gradually causes the heart to lose its pumping capacity.
The researchers used a cutting-edge technique called single-cell RNA sequencing to study human heart tissue from three different types of donors: those who died from doxorubicin-induced heart failure, those who died from heart failure not caused by chemotherapy and those who died from non-cardiovascular causes.
Compared with the other hearts, those with doxorubicin-induced heart failure showed strong patterns of gene activation that blocked removal of dead heart muscle cells and of hyperactivated cells called fibroblasts that produce collagen, creating scar tissue. In the chemo-treated hearts, the molecular culprit behind these damaging effects was elevated CD47, which is also highly present on cancer cells.
The researchers found that treating mice modeling doxorubicin-induced heart failure with an antibody that blocks CD47 allowed helpful immune cells to clear dead cells and reduced scar tissue. The findings could pave the way for new immunotherapy strategies that target CD47 to treat cancer while protecting the heart.