̽��ֱ�� of Cambridge - Xuan Li

Cancer drug could hold hope for treating inflammatory diseases including gout and heart diseases

cjb250 — Wed, 01 Nov 2023 08:00:30 +0000

In a study published on 1 November in the Journal of Clinical Investigation, the researchers have identified a molecule that plays a key role in triggering inflammation in response to materials in the body seen as potentially harmful.

We are born with a defence system known as innate immunity, which acts as the first line of defence against harmful materials in the body. Some of these materials will come from outside, such as bacterial or viral infections, while others can be produced within the body.

Innate immunity triggers an inflammatory response, which aims to attack and destroy the perceived threat. But sometimes, this response can become overactive and can itself cause harm to the body.

One such example of this is gout, which occurs when urate crystals build up in joints, causing excessive inflammation, leading to intense pain. Another example is heart attack, where dead cell build up in the damaged heart – the body sees itself as being under attack and an overly-aggressive immune system fights back, causing collateral damage to the heart.

Several of these conditions are characterised by overactivation of a component of the innate immune response known as an inflammasome – specifically, the inflammasome NLRP3. Scientists at the Victor Phillip Dahdaleh Heart and Lung Research Institute at Cambridge have found a molecule that helps NLRP3 respond.

This molecule is known as PLK1. It is involved in a number of processes within the body, including helping organise tiny components of our cells known as microtubules cytoskeletons. These behave like train tracks inside of the cell, allowing important materials to be transported from one part of the cell to another.

Dr Xuan Li from the Department of Medicine at the ̽��ֱ�� 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.”

But PLK1 also plays another important role in the body – and this may hold the key to developing new treatments for inflammatory diseases.

For some time now, scientists have known that PLK1 is involved in cell division, or mitosis, a process which, when it goes awry, can lead to runaway cell division and the development of tumours. This has led pharmaceutical companies to test drugs that inhibit its activity as potential treatments for cancer. At least one of these drugs is in phase three clinical trials – the final stages of testing how effective a drug is before it can be granted approval.

When the Cambridge scientists treated mice that had developed inflammatory diseases with a PLK1 inhibitor, they showed that it prevented the runaway inflammatory response – and at a much lower dose than would be required for cancer treatment. In other words, inhibiting the molecule ‘calmed down’ NLRP3 in non-dividing cells, preventing the overly aggressive inflammatory response seen in these conditions.

̽��ֱ��researchers are currently planning to test its use against inflammatory diseases in clinical trials.

“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.”

̽��ֱ��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 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.”

Reference
Baldrighi, M et al. PLK1 inhibition dampens NLRP3 inflammasome-elicited response in inflammatory disease models. JCI; 1 Nov 2023; DOI: 10.1172/JCI162129

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 ̽��ֱ�� of Cambridge.

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

kazuma seki (Getty Images)

̽��ֱ��feet of a man suffering from gout - stock photo

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Switching off heart protein could protect against heart failure

cjb250 — Thu, 27 May 2021 07:42:12 +0000

There is an unmet need to find drugs that can successfully improve the heart’s ability to pump blood efficiently after it’s been damaged following a heart attack. However, many drugs that make failing heart muscle contract more strongly have been deemed unsafe, leaving a huge gap in heart attack and heart failure treatment. Scientists now believe that they might have identified a new drug target – a protein called MARK4.

In research funded by the British Heart Foundation (BHF), Cambridge scientists found levels of MARK4 were elevated in mouse hearts after a heart attack. When they compared mice with and without MARK4 in the heart, they found hearts without the protein were 57 per cent better at pumping blood. This protective effect was seen 24 hours after a heart attack and lasted for the entire follow-up period of four weeks.

̽��ֱ��team identified for the first time that MARK4 fine-tunes a structural network within the heart muscle cell – called the microtubule network – that attaches to the machinery which makes heart muscle cells contract and relax. When MARK4 levels were increased after a heart attack, microtubules were tightly anchored onto the contractile machinery in the heart, causing more resistance and preventing them from functioning normally. When MARK4 levels were reduced, microtubules were loosely anchored, making it easier for the heart to contract and relax.

After a heart attack, in the heart muscle cells of mice without MARK4, the speed of contraction increased by 42 per cent and the speed of relaxation increased by 47 per cent, compared to muscle cells from mice with the MARK4 protein. They were also close to functioning at the same level as healthy heart muscle cells, showing the power of lowering levels of MARK4.

Now, the researchers suggest that drugs to switch off MARK4 could provide a promising new way to improve recovery and help the heart to pump blood more efficiently in people with failing hearts.

Dr Xuan Li, BHF Intermediate Research Fellow at ̽��ֱ�� of Cambridge BHF Centre of Research Excellence, said: “After years of research we’ve revealed an entirely new and promising way that could help the recovery of failing hearts.

“It’s early days, and we now need to test the longer-term effects of switching off MARK4. But if drugs to do that prove successful, the life-changing benefits could be seen in people with other types of heart disease as well as those who’ve had a heart attack and developed heart failure.”

Professor Metin Avkiran, Associate Medical Director at the British Heart Foundation, said: “Heart attacks are a major cause of disability worldwide - people who’ve had a major heart attack are at much greater risk of developing chronic heart failure. There are around 920,000 people living with heart failure in the UK, and we desperately need drugs to drastically improve the heart’s function in these patients.

“These findings are a positive step forward. Further research is needed to refine and test drugs that can target MARK4 before we’ll see them given to people who’ve had a heart attack and develop heart failure.”

This study was also supported by the Isaac Newton Trust, Wellcome, Cancer Research UK and the German Research Foundation.

Reference
Yu, X et al. MARK4 controls ischaemic heart failure through microtubule detyrosination. Nature; 26 May 2021; DOI: 10.1038/s41586-021-03573-5

Adapted from a press release by the British Heart Foundation.

Switching off a heart muscle protein could provide a new way for drugs to combat heart failure in people who’ve had a heart attack, according to research led by the ̽��ֱ�� of Cambridge and published in the journal Nature.

After years of research we’ve revealed an entirely new and promising way that could help the recovery of failing hearts

Xuan Li

geralt

Heart graphic

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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