Promising Cancer Drug for Gout, Heart Diseases and More

A cancer drug currently in the final stages of clinical trials could offer hope for the treatment of a wide range of inflammatory diseases, including gout, heart failure, cardiomyopathy, and atrial fibrillation, say scientists at the University of Cambridge.

The researchers identified a molecule that plays a significant role in generating inflammation in response to potentially dangerous chemicals in the body in a study published today in the Journal of Clinical Investigation.

We are born with an immune system known as innate immunity, which serves as the body’s initial line of defense against potentially dangerous substances. Some of these elements will come from outside the body, such as bacterial or viral infections, while others will be formed within it.

“We believe [our findings] could be important in preventing a number of common diseases that can cause pain and disability and in some cases can lead to life-threatening complications” – Xuan Li

Innate immunity causes an inflammatory response with the goal of attacking and destroying the perceived threat. However, this response can become hyperactive and cause injury to the body.

Gout is one such example, which arises when urate crystals accumulate in joints, causing severe inflammation and acute discomfort. Another example is a heart attack, in which dead cells accumulate in the wounded heart – the body perceives itself to be under assault and responds with an overly aggressive immune system, inflicting collateral damage to the heart.

Several of these disorders are characterized by the overactivation of an inflammasome, a component of the innate immune response, notably the inflammasome NLRP3. Cambridge scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute

PLK1 is the name of this molecule. It participates in a variety of functions throughout the body, including the organization of microscopic components of our cells known as microtubules cytoskeletons. These function inside the cell like railroad lines, allowing vital materials to be transferred from one section of the cell to another.

Dr Xuan Li from the Department of Medicine at the University of Cambridge, the study’s senior author, said: “If we can get in the way of the microtubules as they try to organise themselves, then we can in effect slow down the inflammatory response, preventing it from causing collateral damage to the body. We believe this could be important in preventing a number of common diseases that can cause pain and disability and in some cases can lead to life-threatening complications.”

However, PLK1 also performs a crucial role in the body, which may hold the key to finding new treatments for inflammatory illnesses.

Scientists have known for some time that PLK1 is involved in cell division, or mitosis, a process that, when faulty, can result in rapid cell division and the development of tumors. As a result, pharmaceutical companies are testing medicines that block its function as potential cancer treatments. At least one of these medications is in phase three clinical trials, which are the final phases of examining a drug’s efficacy before it may be approved.

When the Cambridge researchers gave a PLK1 inhibitor to mice that had developed inflammatory illnesses, they found that it halted the uncontrolled inflammatory response – and at a considerably lower dose than would be necessary for cancer treatment. In other words, blocking the molecule ‘calmed down’ NLRP3 in non-dividing cells, reducing the excessive inflammatory response seen in these settings.

Clinical trials for its application against inflammatory illnesses are now being planned by the researchers.

“These drugs have already been through safety trials for cancer – and at higher doses than we think we would need – so we’re optimistic that we can minimise delays in meeting clinical and regulatory milestones,” added Dr Li.

“If we find that the drug is effective for these conditions, we could potentially see new treatments for gout and inflammatory heart diseases – as well as a number of other inflammatory conditions – in the not-too-distant future.”

The research was funded by the British Heart Foundation. Professor James Leiper, Associate Medical Director at the British Heart Foundation said: “This innovative research has uncovered a potential new treatment approach for inflammatory heart diseases such as heart failure and cardiomyopathy. It’s promising that drugs targeting PLK1 – that work by dampening down the inflammatory response – have already been proven safe and effective in cancer trials, potentially helping accelerate the drug discovery process.

“We hope that this research will open the door for new ways to treat people with gout and heart diseases caused by overactive and aggressive immune responses, and look forward to more research to uncover how this drug could be could be repurposed.”

For more information:  PLK1 inhibition dampens NLRP3 inflammasome-elicited response in inflammatory disease models. JCI