Researchers have determined that a specific protein, GDF15, is associated with changes in body composition, fat and muscle loss among people with non-small-cell lung cancer following relapse. A researcher says that GDF15 could become a target for drugs to improve the survival of people with cancer.
People with non-small-cell lung cancer often struggle not only with the cancer itself but also with several other conditions.
One is cancer-associated cachexia (CAC), which is characterised by fatigue, weakness and loss of muscle and/or fat tissue and poorer survival.
GDF15 has previously been found among people with anorexia and cancer and may be a promising drug target for CAC and thereby also have exciting potential for treating people with cancer.
“No drugs are globally approved for CAC, and we still know little about the biology behind it. This study therefore aimed to learn more about the biological and genetic associations with the development of CAC, so that we may begin to identify ways to treat it better in the future,” explains a researcher behind the study, Mariam Jamal-Hanjani, Professor, University College London Cancer Institute, United Kingdom.
The research has been published in Nature Medicine.
Four of five people with cancer develop CAC
CAC is a well-known and common disorder affecting people with such diseases as cancer, heart failure, HIV and kidney and lung disease.
CAC can prove to be deadly for people with non-small-cell lung cancer, because the loss of muscle and fat tissue can make them so weak that they cannot cope with the often aggressive cancer treatment. When doctors have to scale back treatment, this increases the risk of succumbing to the disease.
CAC can also be fatal in itself, when the muscles in the chest or heart become too weak to inflate the lungs or make the heart beat.
Up to 80% of the people with late-stage cancer develop some form of CAC, but it remains difficult to diagnose accurately or early on since no good biomarkers exist.
651 participants in a major study
The researchers wanted to determine whether people with non-small-cell lung cancer who develop CAC when the cancer returns after surgery differ in protein expression or genetic expression from people in the same situation but who do not develop CAC.
The researchers therefore analysed computed tomography (CT) images taken from 651 people at the point of non-small-cell lung cancer diagnosis from the Tracking Non-small-cell Lung Cancer Evolution through Therapy (Rx) Lung Study (TRACERx). CT scans are already part of doctors’ toolbox to monitor whether the cancer returns after surgery and during follow-up.
Of these 651 patients, more than 200 had CT scans at both diagnosis and relapse. The researchers used the CT scans to enable advanced computer models to determine how much fat tissue and muscle tissue each participant had, and by comparing CT scans over time, the researchers also determined who lost muscle mass and fat tissue between diagnosis and relapse.
Based on the scans, the researchers identified the participants who developed CAC on relapse.
The researchers also carried out genetic profiling of the lung tumours, including gene expression, and protein expression in blood to determine whether they could identify differences between participants with and without CAC.
“We examined the scans and/or changes in weight at the time of diagnosis and when the cancer returned. In this study, we compared almost 250 participants, with about half having CAC at relapse,” says Mariam Jamal-Hanjani.
GDF15 also recognisable in anorexia
The researchers found several factors that differentiated participants with and without CAC.
CAC was associated with higher levels of inflammation and distinct genetic changes and patterns of gene expression in the tumours.
Perhaps most interestingly, the researchers found that participants with CAC had much higher concentrations of GDF15 in their blood than participants without CAC.
GDF15 is a known mediator of anorexia and weight loss. Likewise, some studies have shown that chemotherapy-associated nausea and vomiting are also associated with an increase in the concentration of GDF15 in the blood.
Anti-GDF15 antibodies are being tested
Another discovery was that participants with less fat tissue and less muscle mass at the time of cancer diagnosis had a greater risk of relapse following surgery.
Muscle mass and fat tissue could thus be a marker for how an individual will fare and who might do well and poorly in the disease trajectory.
Mariam Jamal-Hanjani thinks that the findings may have great perspectives.
She says that several clinical trials are already underway with antibodies to inhibit GDF15.
These potential drugs may counteract CAC, thereby making people with cancer more resilient to treatment.
Another potential is improving studies of the effects of CAC and other cancer comorbidities by integrating data sources in the studies.
“We hope that this idea of integrating genetics, blood test results and clinical images in future studies may help to improve understanding of what drives CAC, so that we can better diagnose it and treat the people who have it before it claims their lives,” concludes Mariam Jamal-Hanjani.
