Repurposed cancer drug shows promise

For this study, researchers began by looking for potential CaMKII inhibitors.

“CaMKII is abundant in heart muscle cells where under physiological circumstances it promotes performance,” Dr. Mark Anderson, Executive Vice President for Medical Affairs, Dean of the Division of the Biological Sciences (BSD) and Dean of the Pritzker School of Medicine at the University of Chicago, IL, and senior author of this study explained to Medical News Today.

“For example, CaMKII contributes to heart rate increases and improved muscle performance, as part of a ‘fight or flight’ stress response,” he said.

“However, excessive CaMKII activity causes electrical instability of the heart muscle cell membranes — mostly by activating electrical proteins called ion channels. Inhibiting CaMKII stabilizes the cell membrane currents, thereby preventing or stopping arrhythmias,” he explained.

During their research, Dr. Anderson and his team identified five previously unknown CaMKII inhibitors out of 4,475 potential medications.

Of those five, ruxolitinib was reportedly the most effective, which, Dr. Anderson said, was surprising to them.

“First, we did not have a clear expectation that any of the screened drugs would have potently inhibited CaMKII,” he said.

“That said, we were not surprised that a kinase inhibitor drug could ‘cross over’ to inhibit CaMKII. However, ruxolitinib is a JAK1/2 inhibitor and these kinases are not closely related to CaMKII. Thus, we would have anticipated that an inhibitor targeting a more closely related kinase would have been identified,” he continued.

Using both cell and mouse models, scientists found just a 10-minute application of ruxolitinib was enough to prevent catecholaminergic polymorphic ventricular tachycardia (CPVT) — a condition that causes cardiac arrhythmia in children — and rescue atrial fibrillation.

Researchers stated they believe new drugs based on their findings could be used in a variety of ways, including when atrial fibrillation symptoms first start to treating children with catecholaminergic polymorphic ventricular tachycardia, who are many times resistant to standard treatments.

The researchers also mentioned there has been some apprehension in developing therapies targeting CaMKII inhibition as CaMKII plays a vital role in brain function, including learning and memory.

However, Dr. Anderson and his team reported the mice treated with ruxolitinib did not show any adverse cognitive effects when tested with memory and learning tasks.

“We think this finding may reduce concerns by drug developers in pharma and biotech that CaMKII is not a viable therapeutic target. Off-target actions of CaMKII inhibition on learning and memory have been a major concern,” Dr. Anderson said.

After reviewing this study, Dr. Stephen Tang, a board certified cardiac electrophysiologist at Providence Saint John’s Health Center in Santa Monica, California, who was not involved with this research, told Medical News Today it was “very exciting” to hear about new potential targeted therapies for genetic arrhythmia syndromes, such as catecholaminergic polymorphic ventricular tachycardia.

“This is an inherited genetic condition that affects calcium release in the heart and often leads to dangerous ventricular arrhythmias. It usually manifests in adolescence and can lead (to) syncope and sudden death. Our current management is very limited and is intended to control the disease, not target the underlying cause,” he explained. “

Dr. Tang commented he always approaches these small animal studies with caution.

“It is a promising proof of concept but involves animals — in this case, mice — and not humans. It is done in a lab and does not always reflect real-life conditions. Certainly, while it shows promise, there needs to be much larger studies (that) will need to show efficacy and safety in both animals and humans to be considered for clinical use,” he said.

Medical News Today also spoke with Dr. Sameer Jamal, a clinical cardiac electrophysiologist and program director of the cardiovascular diseases fellowship at Hackensack University Medical Center, who was also not involved with this research. Dr. Jamal said he was excited and encouraged to hear about this study, as it implies a potential for innovative medicines that will help us better treat cardiac arrhythmias.

“Although this study shows promise, prior use of these agents suggests potential issues (in particular) with toxicities and cognition. Continued evaluation in more carefully conducted, patient-centered settings will hopefully corroborate positive results and mitigate concerns regarding side effects,” he added.