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Detecting myeloma earlier

Several research projects are underway in Oxford focusing on different points in the clinical care pathway to improve myeloma early detection.

Following the cancer metabolomic breadcrumb trail

By analysing the metabolic molecules that tumour cells leave behind, Dr James Larkin is investigating the applications of metabolomics in the early detection of many cancers.

New sequencing methods for distinguishing DNA modifications

Chemical modifications made to the DNA base cytosine play an important role in the regulation of gene expression across the genome. Cytosine can be chemically modified in four ways, with 5-methylcytosine (5mC) being the most common. Demethylation of 5mC by the TET family of enzymes results in the stable intermediates 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxycytosine (5caC). From what has been discovered so far, these modifications appear to have distinct functions. For example, 5mC is associated with repressed regions of the genome whereas 5hmC is present in active ones. However, to study these modifications further, robust sequencing methods are needed that can detect each of these four modifications specifically.

The traditional gold standard method for detecting DNA methylation is bisulphite sequencing. However, this relies on a harsh chemical treatment that degrades most of the DNA sample and is an indirect detection method, which decreases sequencing quality. Recently, a bisulphite-free method called TAPS has been developed by Ludwig Oxford’s Song lab, which has the advantage of preserving more of the DNA, increasing sensitivity, and directly detecting modified cytosines for improved DNA sequencing quality.

Despite its advantages, TAPS cannot distinguish between the different types of cytosine modifications. Other methods already exist that can do so but these use subtraction, for example, measuring 5mC and subtracting this signal from a combined measure of 5mC and 5hmC to obtain 5hmC levels. In addition to the disadvantages of using bisulphite and/or indirect detection strategies, these subtraction methods also need higher sequencing depths and generate very noisy data that can be difficult to interpret. New subtraction-free methods are therefore needed to specifically, directly and sensitively detect these four cytosine modifications in the genome.

In this paper published in Nature Communications, Dr Yibin Liu from Dr Chunxiao Song’s lab (Ludwig Oxford) and Dr Zhiyuan Hu from Professor Ahmed Ahmed’s lab (Weatherall Institute of Molecular Medicine and Nuffield Department of Women’s and Reproductive Health, University of Oxford) have developed a suite of TAPS-related whole genome sequencing methods for specifically detecting 5mC, 5hmC, 5fC and 5caC. They have named these TAPSβ (for 5mC), chemical-assisted pyridine borane sequencing (CAPS; for 5hmC), pyridine borane sequencing (PS; for 5caC and 5fC) and pyridine borane sequencing for 5caC (PS-c; for 5caC).

With these new methods, the research community is now armed to tackle more of the questions about the distinct and important functions of cytosine modifications in the genome and how their distribution is altered in diseases such as in cancer.

Bowel cancer patients going undiagnosed due to COVID distruption

A new study led by the University of Oxford has found that since the first coronavirus lockdown the number of people diagnosed with bowel cancer in England has fallen sharply, with a deficit persisting up to October 2020.

Between April and October 2020, over 3,500 fewer patients than expected were diagnosed with bowel cancer in England. Since bowel cancer is more likely to be curable if it is detected at an early stage, these results suggest that many patients, whose diagnosis has yet to be made, may die unnecessarily. The results are published today in The Lancet Gastroenterology & Hepatology.

The research was carried out by a team of clinicians and academic researchers from across the UK, including from the University of Leeds and the University of Newcastle.

For this study, the researchers assessed the patterns of referral for bowel cancer investigation, diagnosis and treatment within the English NHS from 1 January 2019 to 31 October 2020.

The results showed that, compared with an average month in 2019, during April 2020 at the peak of the first wave of coronavirus:

  • the monthly number of referrals by GPs to hospital clinics for investigation of possible bowel cancer reduced by 63% (from 36,274 to 13,440);
  • the number of colonoscopies performed fell by 92% (from 46,441 to 3,484); and
  • the monthly number of people with confirmed bowel cancer referred for treatment fell by 22% (from 2,781 to 2,158), and the number of operations performed fell by 31% from (2,003 to 1,378).

This is the first study to assess the impact of the COVID-19 pandemic on the diagnosis and management of bowel cancer across England.

Full story available on the Nuffield Department of Population Health website.

“The Oxford Classic” classification system uncovers new information about ovarian cancers

In 2020, using single cell RNA sequencing, Oxford cancer researchers made a breakthrough by identifying  new types of Fallopian tube cells that are the cells of origin for the majority of ovarian cancers. They showed that that the types of these newly-discovered non-cancer cells are “mirrored” into different ovarian cancer subtypes. These subtypes correlated well with survival.

Discovering the new subtypes of cells have allowed Oxford researchers to classify and categorise tumours based on their origin in the body, and determine which ones can lead to more severe cancer outcomes – an approach which has been dubbed the ‘Oxford Classification of Carcinoma of the Ovary’ or ‘Oxford Classic’ for short. The Oxford Classic will provide much more accurate predictions for disease outcome in patients, as well as helping researchers to develop targeted therapies for each type of cancer

Professor Ahmed Ahmed, Nuffield Department of Women’s and Reproductive Health and originator of the Oxford Classic, has how published a paper in collaboration with Imperial College, demonstrating the applications of the Oxford Classic approach. As well as shedding light on some previously unknown information about ovarian cancers.

Professor Ahmed says:

“Our group is very excited that we were able to confirm the predictive role of the Oxford Classic. This work highlights that it is now important to identify new personalised therapies for the Oxford Classic-defined EMT-high ovarian cancer subtype. The finding that there is a strong connection with abundant M2 Macrophages already offers a good hint as to where we could find good treatment options for patients with this type”.

Serous ovarian cancer (SOC) is the most common cancer subtype, but is challenging to classify and predict its prognosis. Using the Oxford Classic, researchers found that specific SOC subtypes, known as EMT-high types, were associated with a lower survival rate in serous ovarian cancer patients.

Professor Christina Fotopoulou of Imperial College London says:

“This has been a very fruitful collaboration between two major UK gynaecological cancer centres; Oxford and Imperial College. We have generated very promising results towards an individualisation of care of our ovarian cancer patients. Our data will help clinicians to stratify patients to the right treatment pathway based on features of tumour biology of their disease. I hope we can continue to work together on that basis and expand and validate our data further also on a larger scale.”

EMT stands for epithelial-mesenchymal transition, it is the process by which epithelial cells change and become more mobile. This mobility provides the cells with the opportunity to spread leading to cancer progression. EMT-high subtypes are tumours that have a high number of cancer cells with greater mobility.

Researchers also found that EMT-high subtypes were associated with abundance of a type of immune cells called M2 macrophage. M2 macrophages possess immunosuppressive properties, and can lead to poorer treatment responses if they are found in high quantities within a tumour. It has previously been observed that patients with high-EMT tumours had a poor immune response. This study confirms that the EMT-high subtypes are associated with an immunosuppressive environment (and so poor patient responses to treatment) due to their association with more M2 macrophages – a link that has not previously been identified.

Whether M2 macrophages induce the EMT level or the EMT level results in higher levels of M2 macrophages will be an important question to be addressed by Prof Ahmed’s future work. However, this study has demonstrated the Oxford Classic’s strong ability to predict a patient’s prognosis.

Classifying the EMT status of a tumour, using the Oxford Classic, could potentially become a valuable part of future cancer stratification methods. This will ensure that appropriate treatment methods and attention are given to patients with a poorer overall prognosis.

Ovarian Cancer Action’s CEO, Cary Wakefield, says

“While other cancers have achieved major improvements in treatment outcomes, ovarian cancer continues to go unrecognised, underfunded, and misdiagnosed. The Oxford classic is an exciting breakthrough that will help to identify new treatment options for ovarian cancers that have a lower chance of survival. Funding important research like this will bring us closer towards a shared goal of more women surviving ovarian cancer”.

About the study

This study was co-led by Prof Ahmed Ahmed of the University of Oxford and Prof Christina Fotopoulou of Imperial College. It was funded by Ovarian Cancer Action, CRUK Oxford Centre and the National Institute for Health Research (NIHR) Biomedical Research Centre.

This study has demonstrated the potential of the Oxford Classic to:

  1. Accurately classify types of serous ovarian cancers
  2. Identify populations of cancer cells that have poorer prognoses (such as EMT high cancers)

Ahmed Ahmed is a Professor of Gynaecological Oncology at the Nuffield Department of Women’s & Reproductive Health at the University of Oxford and a Consultant Gynaecological Oncology Surgeon at the Oxford Cancer and Haematology Centre. His work focuses on surgical, medical and fundamental research into ovarian cancer, its early detection, treatment and screening.

Read the fully study here: http://clincancerres.aacrjournals.org/content/early/2021/01/12/1078-0432.CCR-20-2782

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.

SCALOP team discover new pancreatic cancer biomarker

The discovery of pancreatic cancer biomarkers (naturally occurring molecules, genes or characteristics which can be used to confirm the presence or predict the outcome of a cancer) is vital in understanding patient outcomes and finding new therapeutic targets. In recent years, improved understanding of the biology of pancreatic cancers has resulted in new combination therapies being developed, including the development of the first successful biomarker-guided therapy in pancreatic cancer known as the POLO trial.

A recent paper from the SCALOP-1 trial team, led by Prof. Somnath Mukherjee, was published in BJC Nature, which has identified proteins that could act as a new biomarker to predict a patient’s outcome from pancreatic cancer. The chemokine protein known as CCL5, found circulating in patient blood, was found in low quantities in patients with better overall pancreatic cancer survival (around 18.5 months, rather than less than a year).

It is already known that CCL5 is involved in tumour invasion, tumour metastasis and the creation of an immune-system-suppressing micro-environment that allows pancreatic cancer to develop quickly. Its identification as a biomarker makes CCL5 a perfect new target for potential drug treatments. For example, blockade therapies that target the CCL5-CCR5 pathway and reduce the presence of CCL5, may produce new opportunities to improve the outcome of other immunotherapies that pancreatic cancer patients are undergoing.

Co-lead of this study, Prof Eric O’Neil from the Department of Oncology, is now investigating combination of CCL5 antagonist drugs with immunotherapy and radiotherapy drugs in animal models, which he hopes will lead to the development of new, more-effective pancreatic treatments in the future.

Next steps for the SCALOP trials

When pancreatic cancer has developed beyond a stage where it is operable, the only option for patients is often chemotherapy or chemoradiotherapy (the combination of chemo and radio therapy). The creation of new combination drugs used in the chemotherapy process has led to some improvement in overall length of patient survival of pancreatic cancer, which remains one of the highest causes of cancer death in the UK, however the use of these drugs is limited by the toxic effect on the body.

Following on from the SCALOP-1 trial, the SCALOP-2 trial, has been run from the University of Oxford, hosted through the Oncology Clinical Trials Office and lead by Prof Somnath Mukherjee. It has completed recruitment earlier in the year and final results are awaited.

Currently in the UK, chemoradiotherapy for locally advanced pancreatic cancer consists of 28 daily treatments of radiotherapy. Although this treatment is effective in controlling local symptoms and slowing down local cancer progression, in most cases it is unable to remove the cancer or shrink it well enough to make it operable. There is a need to find more efficient treatment combinations to improve patient outcomes.

The SCALOP-2 clinical trial compared different ways of combining chemotherapy and chemoradiotherapy to see which combination provides the most benefit to patients who have inoperable pancreatic tumours. This includes testing radiotherapy dose escalation and the use of nelfinavir as a radiosensitizer drug – something that makes tumour cells more sensitive to the effects of radiation therapy. In doing so, it is hoped that researchers can uncover more efficient drug combinations for patients with pancreatic tumours that are inoperable.

Blood and biopsy samples have been collected as a part of SCALOP-2 trial, in order to allow the team to take a more detailed look at proteins, DNA and cells involved in the cancer and how they are affected by treatment. This will tell researchers much more about how a patient’s type of cancer behaves and how it has responded to various treatments, allowing for the discovery of biomarkers just like CCL5 from the SCALOP-1 trial.

More information about the SCALOP-2 trial can be found on the Pancreatic Cancer UK website here.

Detecting pancreatic cancer through blood tests

Pancreatic ductal adenocarcinoma (PDAC) makes up 95% of all pancreatic cancer cases and has the lowest survival rate, and early diagnostic methods have yet to be developed. As a result, diagnosis often comes at a later stage when treatment options are limited and prognosis is poor.

Diagnosis at this stage often comes from imaging techniques followed by tissue biopsies, which are not appropriate options to use as standardised, early screening methods. New ways to diagnose PDAC at an earlier stage are needed, without the use of invasive procedures.

Liquid biopsies are becoming a more popular option to fill this demand. Taking a blood sample is minimally invasive, quick, and can tell us a lot of information about a person from their cfDNA (cell free DNA). cfDNA is released from cells and circulates in the blood, containing information about the cell they come from.

Methylation on cfDNA often appears in cancer patients, making it an effective biomarker that can be used to diagnose the presence of cancer with high accuracy and specificity about the cancer (such as location). The concept has many applications, including in the earlier diagnosis of PDAC.

The identification of these biomarkers in blood is often limited to the technology used, with DNA being damaged by the harsh chemicals that are used in the processing. The recent development of TAPS technology at the University of Oxford has helped to overcome this, using a bisulphate-free method, and making it a perfect method for PDAC biomarker identification.

DPhil students Paulina Siejka-Zielinska and Felix Jackson and Postdoctoral Researcher Jingfei Chang from Dr Chunxiao Song’s lab in collaboration with Dr Shivan Sivakumar (consultant medical oncologist) have been investigating TAPS as a method to identify PDAC biomarkers. Using blood samples from PDAC patients and healthy individuals, they are applying TAPS technology to prove that it can be used to accurately detect pancreatic cancer biomarkers in cfDNA.

Preliminary results from this study suggest that cfDNA methylation can be used for the identification of PDAC, as well as being able to accurately distinguish between pancreatic cancer and other pancreatic disorders that effect the DNA, such as pancreatitis.

If this is the case, then the results from this study will make for solid grounds for the application of TAPS in the earlier screening for pancreatic cancer.

About the Song Lab

The Song Lab combine various chemical biology and genome technologies to develop novel tools to analyse the epigenome. The lab apply these tools to two main research areas: the use of epigenetic modifications in circulating cell-free DNA from the blood for non-invasive disease diagnostics including early detection of cancer, and understanding the contribution of epigenetic heterogeneity in cancer development.

Most recently, the TAPS technology developed at the Song Lab has led to the creation of the start up Base Genomics, which has been launched to set a new gold standard in DNA methylation detection using this TAPS technology. Base Genomics will initially focus on developing a blood test for early-stage cancer and minimal residual disease. You can read more about it here.

$410 million buy out for Oxford cancer detection technology

Biotechnology company, Base Genomics, launched in June 2020 based on Oxford’s Dr Chunxiao Song’s innovative TET-assisted pyridine borane sequencing (TAPS) technology. This week, Base Genomics was bought out by Exact Sciences for $410 million.

TAPS is a new method for measuring DNA methylation, a chemical modification on cytosine bases. DNA methylation is frequently altered in cancer and these altered DNA methylation levels are preserved in the small amounts of DNA that are released into the blood from cancer cells. With its enhanced sensitivity over the standard methodology for measuring DNA methylation, TAPS has great potential as the basis for a multi-cancer blood test.

“This acquisition by Exact Sciences will enable us to accelerate the clinical and commercial development of Base Genomics and unlock a new era for early cancer detection. This is a big step forwards”

says Base Genomics co-founder and chemistry lead, Dr Yibin Liu, who co-invented the technology while a post-doc at the Ludwig Institute for Cancer Research, Oxford Branch.

Exact Sciences will continue to build on the Base Genomics team in Oxford, creating a world-leading research centre for early stage cancer detection.

“I am thrilled that the TAPS technology developed in my lab has received this level of investment. We can now proceed much more rapidly to fully leverage the power of this technology for cancer detection and patient benefit”

says Dr Chunxiao Song, Assistant Member of the Ludwig Institute for Cancer Research, Oxford Branch and Base Genomics co-founder.

Chunxiao Song’s research has received funding from the Ludwig Institute for Cancer Research, Cancer Research UK and the NIHR Oxford Biomedical Research Centre. TAPS is continuing to be developed in Chunxiao’s lab, for example it was recently adapted for long-read sequencing, to further its application to other fields of biomedical research.

Understanding breast cancer risk in Chinese populations

Obesity has long been associated with an increased risk of breast cancer in post-menopausal women. But the relationship between obesity and breast cancer is less clear in pre-menopausal women. Moreover, a lot of uncertainty remains around the associations between body weight and breast cancer in countries such as China, where the average BMI is lower than in western countries, along with differences in the prevalence of other risk factors between western and eastern cultures. There is a need to better understand how morphological and lifestyle differences between populations may influence cancer incidence, in order to better understand and identify who is at an increased risk.

An upcoming study from the Clinical Trial Service & Epidemiological Studies Unit (CTSU) at the Nuffield Department of Population Health, led by Dr Christiana Kartsonaki and Dr Ling Yang, is investigating breast cancer incidence in Chinese populations in relation to adiposity measures such as BMI, waist circumference and body fat percentage.

The team used data from the China Kadoorie Biobank, a cohort study that has collected information from over half a million individuals from China since 2004. During an average of 10 years of follow-up of this cohort, there were 2,053 cases of breast cancer, which allows the team to assess what demographic or lifestyle factors might be influencing risk in Chinese women.

Early results suggest that, like western populations, increased levels of adipose tissue leading to higher BMIs are associated with higher risks of breast cancer in Chinese women, particularly among post-menopausal women. These results highlight the importance of understanding relative cancer risk factors between different ethnicities. Whilst some factors such as obesity are often common causes of cancer across all populations, there are many key biological and lifestyle factors that differ between western and eastern populations. Understanding how these may impact cancer risk in different ways will allow researchers to inform policy, so that clinicians may better identify who may have a higher risk of developing cancer.

About the CTSU

The Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU) aims to generate and disseminate reliable evidence from observational epidemiology and from randomised trials that leads to practicable methods of avoiding premature death and disability.

This project is being led by Dr Christiana Kartsonaki and Dr Ling Yang in conjunction with Prof. Zhengming Chen.