Experimental Cancer Drug May Also Treat Heart Failure

Investigational cancer drug blocks inflammation and fibrosis in heart cells.

Patients with heart disease are required to take daily medications to ensure that their condition does not progress. Unfortunately, nearly half of patients with heart failure die within 5 years of diagnosis. Although there are numerous treatments for the condition, there is an unmet need for novel therapies.

In a new study published by Science Translational Medicine, the authors explored a new way to treat patients with heart failure.

"The current standard of care is clearly not sufficient, which highlights the urgent need for new therapeutic approaches," said senior study author Saptarsi Haldar, MD. "In our previous work, we found that a drug-like small molecule called JQ1 can prevent the development of heart failure in mouse models when administered at the very onset of the disease. However, as the majority of patients requiring treatment already have longstanding cardiac dysfunction, we needed to determine if our strategy could also treat established heart failure."

The authors are already exploring the use of JQ1 in humans with cancer. The drugs inhibit the BRD4 protein, which is in the BET bromodomains family and directly impacts heart failure.

In the new study, the authors discovered that JQ1 can treat severe, long-term heart failure in both small animals and cell models. The drug treats this condition by inhibiting inflammation and fibrosis, which are key drivers of heart failure, according to the study.

"It has long been known that inflammation and fibrosis are key conspirators in the development of heart failure, but targeting these processes with drugs has remained a significant challenge," Dr Haldar said. "By inhibiting the function of the protein BRD4, an approach that simultaneously blocks both of these processes, we are using a new and different strategy altogether to tackle the problem."

FDA-approved heart failure drugs only work at the surface of heart cells, but JQ1 attacks the underlying cause of the problem and inhibits destructive processes in the nucleus, according to the study. This may make the experimental drug a more efficacious treatment.

"We treated mouse models of heart failure with JQ1, similarly to how patients would be treated in a clinic," said co-first study author Qiming Duan, MD, PhD. "We showed that this approach effectively treats pre-established heart failure that occurs both after a massive heart attack or in response to persistent high blood pressure (mechanical overload), suggesting it could be used to treat a wide array of patients."

To further their analysis, the authors developed cardiomyocytes from induced pluripotent stem cells to determine whether the drug is effective in human cells.

"After testing the drug in mice, we wanted to check whether JQ1 would have the same effect in humans," said co-first author Sarah McMahon. "We tested the drug on human cardiomyocytes, as they are cells that not only beat, but can also trigger the processes of inflammation and fibrosis, which in turn make heart failure progressively worse. Similar to our animal studies, we found that JQ1 was also effective in human heart cells, reaffirming the clinical relevance of our results."

These findings also have positive results for patients with cancer. Compared with other cancer drugs, JQ1 was not observed to cause cardiac toxicity. The authors report that BRD4 inhibitors may be a cancer treatment that can have positive effects on the heart, according to the study.

While additional studies are needed, the authors note that drugs derived from JQ1 are already in clinical testing.

"Our study demonstrates a new therapeutic approach to successfully target inflammation and fibrosis, representing a major advance in the field," Dr Haldar concluded. "We also believe our current work has important near-term translational impact in human heart failure. Given that drugs derived from JQ1 are already being tested in cancer clinical trials, their safety and efficacy in humans are already being defined. This key information could accelerate the development of a new heart failure drug and make it available to patients more quickly."