Scientists closer to understanding the devastating loss of fat and muscle during cancer

Scientists examining the causes of cachexia – the sudden loss of weight, appetite, and muscle that some cancer patients experience in the later stages of the disease, believe they are now one step closer to understanding the causes behind the condition.

The study, part of the BRC-supported TRACERx programme, which is funded by Cancer Research UK, and published in Nature Medicine, found distinct patterns of genes that were much more likely to be found in the tumours of patients with cachexia, and could lead to a way to diagnose the condition before symptoms appear.

They also spotted a high correlation with levels of GDF15 in the blood, a protein which other studies had previously linked with appetite and weight loss. TRACERx researchers said that by targeting GDF15 with treatment they may be able to find a way to manage cachexia or even stop it in its tracks.

TRACERx, a £14m study carried out at the Francis Crick institute, alongside UCL and Dana-Faber Cancer Institute, explores the evolution of cancer in real time – by following patients all the way from diagnosis to either relapse or cure after surgery.

Although the clear link between involuntary weight loss, muscle wasting and fatality has been known since the advent of modern medicine, a clear biological understanding of what is happening in the body when cachexia takes hold has eluded scientists.

Despite up to 80% of patients in an advanced stage of cancer experiencing some degree of cachexia, - it remains complicated to diagnose and there are no globally approved therapies or treatments.

Dr Mariam Jamal-Hanjani, Clinical Associate Professor at UCL Cancer Institute and lead researcher on the study said: “A biological understanding of this devastating condition has long eluded researchers, but the incredible investment and in-depth sample and data collection in TRACERx has allowed us to begin to make discoveries in cachexia. We are particularly excited about trying to find alterations in the cancer or blood that can help identify which patients are at risk of developing cachexia in the future so that we can intervene before this happens.”

The researchers used a cutting-edge AI-assisted method to process hundreds of scans from patients who had relapsed after surgery and who had lost muscle and fat. The scans showed how much muscle and fat patients had in their abdomens. They were able to identify those patients with cachexia (often difficult to diagnose) and carry out a comparison of patients with and without the condition at unprecedented detail.

This process also revealed a link between the distribution of fat at the time of diagnosis and survival - lower levels of body fat at baseline were found to be associated with poorer survival outcomes. The next step will see the researchers building on this work by investigating if cachexia develops in some patients at later stages of disease, and they will examine the tumour and blood samples collected in TRACERx to explore how cancer metabolism and the immune system might play a role in cachexia. They are also hoping to explore whether inhibiting GDF15 could reverse features of cachexia.

Professor Ketan Patel, Chief Scientist at Cancer Research UK said: “This study is a powerful example of what can be achieved when researchers have the space and time to look closely into what happens to our bodies when we have cancer.

“The TRACERx researchers were able to explore these vast amounts of data with open minds and have come away with discoveries that have the potential to make real differences to people with cancer. Cachexia is a condition that’s devastating to patients, it leads to poor quality of life, impairs the ability to tolerate treatment and contributes to mortality. Findings like this will build up the toolkit we need to fight it.”