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DeLIVER clinical research study underway as recruitment opens

DeLIVER is a five-year Cancer Research UK-funded research programme led by Professor Ellie Barnes (Nuffield Department of Medicine) that aims to detect liver cancer earlier. Liver cancer is the fastest rising cause of cancer death in the UK, with more than 5,000 deaths per year. To improve survival, it is crucial to diagnose liver cancer earlier, when current treatments are more likely to be successful. However, this is challenging because symptoms are vague and late-presenting, and are frequently masked by co-occurring liver disease, such as cirrhosis.

A major goal of the DeLIVER programme is to learn more about the biology of liver cancer development and to use this information to design more sensitive detection tests. Because many people being tested for liver cancer have the high-risk condition cirrhosis, these tests need to be specific enough to detect liver cancer on top of other changes in the liver caused by cirrhosis. In order to identify the defining characteristics of early liver cancer, researchers need to perform a detailed molecular analysis of tissue from tumours and the background liver in people with liver cancer and cirrhosis and compare this to liver tissue from people with cirrhosis alone.

The DELPHI (Deep Liver Phenotyping and Immunology) study will recruit 100 participants at Oxford University Hospitals NHS Trust. 80 of these recruited participants will have cirrhosis (caused by hepatitis virus B or C, fatty liver disease or alcohol) and 20-30 participants will have liver cancer in addition to cirrhosis. After giving consent, the participants will undergo fine-needle aspiration to collect tissue from the liver. This is a safe technique established in Oxford as one of only a few centres in the UK. Blood samples will also be taken.

Cancer Research UK Clinical Research Fellow Dr Rory Peters is leading the study. He said,

“We are very pleased to have started the recruitment for the DELPHI study. The in-depth analysis of samples from the DELPHI participants will be critical for increasing our understanding of how liver cancer develops and will give insights into how this cancer can be detected earlier.”

The researchers will look at individual cells to understand the cellular make-up of the tumour and surrounding tissue, including infiltrating immune cells, and how this may influence cancer development. By comparing the tissue from participants with and without cancer, they will also look for changes in protein or metabolite levels and alterations in the levels of chemical modification of DNA by methylation using the TAPS assay developed in Oxford by Dr Chunxiao Song. They will investigate whether the changes that they observe from the tissue analysis can also be detected in the blood, which would provide evidence that a blood-based assay could be developed as a less invasive diagnostic test.

Professor Ellie Barnes, Chief Investigator for DeLIVER said,

“The DELPHI study is one of three clinical projects within the DeLIVER programme. Together, these studies will inform us which of our diagnostic technologies perform best at detecting liver cancer at the earliest stages. We hope this work will lead to a step-change in earlier liver cancer diagnosis and improved patient survival.”

 

Read more about the DeLIVER programme in the OxCODE liver cancer early detection research showcase.

Studying viral genetics to aid liver cancer early detection

Chronic Hepatitis C virus (HCV) infection causes liver damage and is a significant risk factor for liver cancer. There are now cures available for chronic HCV infection and the World Health Organisation has set a target to eliminate HCV by 2030. However, although curing HCV reduces the risk of liver cancer, individuals with a history of chronic HCV infection remain at higher risk.

There are multiple types of HCV that differ in their genetic sequences. Previous research has established that not all HCV genotypes present the same level of risk for liver cancer. The next step is to discover which particular viral genetic motifs are most associated with liver cancer so the HCV-infected individuals who are at the highest risk of liver cancer can be identified. This will enable more targeted surveillance to detect liver cancer earlier when treatment is more likely to be successful.

Professor Ellie Barnes and Dr Azim Ansari (Nuffield Department of Medicine) have been awarded funding as part of a wider Wellcome Trust Collaborative Award led by Professor Graham Foster (Queen Mary’s University, London) to study anti-viral drug resistance and long-term effects of HCV in Pakistan. HCV infection is highly prevalent in Pakistan with up to 20% of the population infected in hotspot regions.

A cohort of ~500 individuals with HCV-associated liver cancer will be recruited and samples will be collected for viral whole genome sequencing. The Oxford team will then analyse these sequences, comparing to people with HCV infection but not cancer, to identify any genetic patterns that are linked to cancer.

This work complements the recently launched Cancer Research UK-funded DeLIVER programme which, among other features, will study host and viral genetics in a cohort of individuals with HCV and liver cancer in the UK.

Investigating the effects of co-morbidities on liver cancer risk

Hepatitis B virus (HBV) infection is one of the world’s leading causes of infection-related death and levels are increasing. A large proportion viral of hepatitis-associated deaths are due to liver cancer and cirrhosis. However, because not everyone with chronic HBV will develop liver cancer, more needs to be understood about the additional risk factors for liver cancer in people with chronic HBV infection. This will allow improved risk prediction for liver cancer, which, in addition to more sensitive diagnostic technologies, is an important part of the strategy for monitoring, to support earlier liver cancer detection and improved survival.

In this review published in the Journal of Viral Hepatitis, Cori Campbell and colleagues from Dr Philippa Matthews’ and Professor Ellie Barnes’ groups (Nuffield Department of Medicine) performed a literature review and meta-analysis to look for evidence of risk factors linked to HBV-associated liver cancer. Given the increasing prevalence of co-morbidities such as diabetes, high blood pressure and kidney disease, and metabolic risk factors such as obesity and dyslipidaemia (abnormal lipid blood profiles), the focus of this review was placed on these risk factors.

The researchers identified 40 studies that showed an association between liver cancer risk in the presence of chronic HBV infection and diabetes, high blood pressure, dyslipidaemia and obesity. Out of all these associated co-morbidities, only diabetes had enough published studies on it to be able to perform further analysis.

The risk of liver cancer was over 25% higher in individuals with chronic HBV infection and diabetes compared to those without diabetes, although there was some variation between the effect of diabetes seen in different studies. This suggests that it may be worth increasing liver cancer screening in individuals with both chronic HBV infection and diabetes. Interestingly, in studies where metformin was given as a treatment for diabetes, the association of diabetes with risk of liver cancer was weakened, warranting further investigation.

The full review article can be accessed on the Journal of Viral Hepatitis website.

For more information about liver cancer early detection research in Oxford, see the liver cancer research showcase.

Prof. Ellie Barnes comments on the 2020 Nobel Prize for Medicine

Prof Ellie Barnes comments on the recent Nobel Prize in Medicine, awarded to Harvey J. Alter, Michael Houghton and Charles M. Rice for their discovery of the Hepatitis C virus, a major global health problem and a cause of cancer

In 1989, Harvey J. Alter, Michael Houghton and Charles M. Rice used what at the time were state-of-the-art technologies available to identify the virus that causes Hepatitis C infection. This ground-breaking discovery allowed for the development of blood tests to diagnose the Hepatitis C Virus (HCV) and saved millions of lives over the last 40 years.

Testing for HCV has enabled the discovery of chronic infections that results from the Hepatitis C virus. Currently 71 million people are living with HCV, as there is no vaccine to prevent infection. HCV remains a silent disease that is often only diagnosed until symptoms of late-stage liver disease develop. In many cases, it goes undetected until severe complications occur, the most serious of which is hepatocellular carcinoma (HCC). By this point, existing treatments are often less effective at clearing the infection.

Hepatocellular carcinoma is the most common type of primary liver cancer, which is common in those who have had liver scarring due to Hepatitis B and C infections. 400,000 people globally die each year from HCV, with hepatocellular carcinoma continually on the rise. As a result, viral hepatitis is still one of the most serious global pandemics at large. Due to the lack of an effective HCV vaccine and early detection methods for the diagnosis of hepatocellular carcinoma, it is crucial to develop techniques that can aid its early detection and thereby increase the survival rate of cancer patients.

Prof Ellie Barnes at the Nuffield Department of Medicine, leads the DeLIVER study for the early detection of hepatocellular carcinoma that builds on the seminal work as recognised with this year’s Nobel Prize. On the topic of this year’s Nobel Prize winners, she says:

“Now, we need to repeat what those Nobel Prize winners did in 1989 for liver cancer. Like them, we can use today’s new advances in imaging and molecular technology to identify hepatocellular carcinoma at an earlier stage when it is still curable.

“The techniques to do this have advanced remarkably over the last 40 years and it should be possible, with carefully designed patient cohorts and inter-disciplinary effective co-working. By building on the work of Alter, Houghton and Rice, we can do it.”

The risk of liver cancer is increased by viral hepatitis infections, alcohol and obesity, causing the immune system to attack the liver leading to scarring and liver cirrhosis. Monitoring of people with these conditions can reduce mortality but current diagnostic tests for hepatocellular carcinoma fail to detect cancer in many cases.

The DeLIVER team is building on the work of Nobel Prize winners through the use of state-of-the-art multiparametric imaging, viral genetics, and liquid biopsy technologies (such as TAPS) to identify the early indicators of liver cancer by studying people at risk, such as those with Hepatitis C, over several years.

About DeLIVER

DeLIVER is a CRUK-funded programme led by Professor Ellie Barnes that aims to better understand the pre-cancerous changes in the liver and use this knowledge to inform new technologies for early HCC detection. The study will receive patient input from the British Liver Trust and the Hepatitis C Trust.

You can read more about it on the OxCODE website here.