Oxford Cancer Centre appoints Prof. Tim Elliott as new co-director

The CRUK Oxford Centre is pleased to announce the appointment of Professor Tim Elliott as its new co-Director. Tim will work alongside Professor Mark Middleton who has filled the role since 2017, to develop and deliver the research strategy for the Oxford Centre.

Professor Tim Elliott is taking over from Professor Xin Lu, who is stepping down after over 3 successful years in the post. During her tenure, Xin has led a step change in the coordination and integration of research efforts across the city. Under Xin’s leadership, a collaborative network of early cancer detection researchers across Oxford has been established and supported through the formation of the Oxford Centre for Early Cancer Detection (OxCODE). As well as providing a forum to stimulate and catalyse research in this critically important research field, significant programmatic funding has been obtained, including for liver (DeLIVER – Prof. Ellie Barnes) and lung (DART – Prof. Fergus Gleeson) cancers, along with numerous seed and project external funding awards in early detection. Xin will continue to play a major role in directing and supporting the CRUK Oxford Centre strategy in her continuing positions as OxCODE Director, NIHR Oxford BRC Cancer Theme Co-Lead and Director of the Ludwig Institute for Cancer Research, Oxford Branch.

Tim has recently joined the Nuffield Department of Medicine and Oriel College as the Kidani Professor of Immuno-Oncology. He re-joins the Oxford community from Southampton University, having previously completed his undergraduate degree in Biochemistry at Balliol and subsequently holding a Professorial post at the Weatherall Institute for Molecular Medicine. Tim brings with him a wealth of expertise and experience in leading international collaborative multidisciplinary research; and he helped lead the campaign for the Southampton Centre for Cancer Immunology which opened in 2018 and where he was Director until his appointment in Oxford. He is ideally placed to help lead the Oxford Centre in its efforts to ensure that cancer research across the city continues to drive improvements in cancer patient care through enhancing our fundamental understanding of the disease.

Professor Tim Elliott, Cancer Research UK Oxford Centre Co-director and Kidani Professor of Immuno-Oncology at the Nuffield Department of Medicine, University of Oxford, said:

“This is a great time to be joining Oxford.  Recent events have demonstrated how effectively Oxford researchers can come together to generate the new knowledge needed to drive life-saving treatments for a new pathogen.  There is every sign that we can focus that collegiality on beating cancer too.

“I am excited by the prospect of helping multidisciplinary teams to converge on difficult problems that will ultimately lead to better clinical outcomes for people diagnosed with cancer.  I am also really looking forward to working with Mark, whose clinical and translational expertise and great leadership will be key to pulling our discovery science through into the clinic.”

 

Professor Mark Middleton, Cancer Research UK Oxford Centre Co-director and Head of Department of Oncology at the University of Oxford, said:

“I am delighted that Tim will help lead our diverse research community. His successful approach to delivering internationally recognised multi-disciplinary immunology research makes him an exciting addition to Oxford. Tim joins us a fascinating time, with more opportunities than ever for ensuring that cancer patients benefit from the world-leading research being carried out across Oxford. His track record of bringing together fundamental, translational and clinical researchers that span traditional research boundaries will be critical in building on our recent progress exploiting Oxford’s cancer research ecosystem to improve patient care worldwide.

“The leadership Xin has provided to the Cancer Centre over the last 3 years has been transformative. There are many clinical trials and early detection programmes that would not have taken place without her, and this is testament to both her strategic vision and the time and effort she has put into the Centre during her tenure. I’d like to thank Xin on behalf of all the researchers across Oxford who have benefited from her leadership. I look forward to continuing to work with her on delivering the Centre’s goals in her capacity as OxCODE Director, NIHR Oxford BRC Cancer Theme Co-Lead, and Director of the Oxford Branch of the Ludwig Institute for Cancer Research.”

 

A very warm welcome to Professor Tim Elliott from the CRUK Oxford Centre team and wider cancer research community here in Oxford.

Professor Tim Elliot Biography

Professor Tim Elliott left the University of Oxford with a first in Biochemistry in 1983, received a PhD from the University of Southampton in 1986 and completed his postdoctoral training at MIT. He held a lectureship and later a professorship in immunology (Weatherall Institute for Molecular Medicine and Balliol College, University of Oxford) between 1990-2000 before being appointed to the Chair of Experimental Oncology, School of Medicine, University of Southampton.

He was Associate Dean (Research) for the Faculty of Medicine between 2005 and 2015. He’s held appointments on Scientific Advisory boards at the Wellcome Trust, the Association of International Cancer Research, Leukaemia and Lymphoma Research, Symphogen, and Avviity Therapeutics; chairs the CRUK Expert Review Group for Cancer Immunology and sits on the CRUK Discovery Science Research Committee. He has published over 130 papers in the field of molecular immunology; was visiting lecturer of the Alberta Heritage Foundation for Medical Research, University of Edmonton, Alberta in 1999; and recently held a visiting Professorship at the Netherlands Cancer Institute, Amsterdam. He is a fellow of the Royal Society of Biology and in 2014 he was elected to the Academy of Medical Sciences.

Professor Elliott was amongst the key group of immunologists who developed studies of antigen presentation at the molecular level during the 1990s, undertaking a series of studies to determine and define the immunostimulatory properties of MHC Class I molecules and elucidating the molecular mechanisms of co-factor assisted peptide loading of MHC Class I in antigen presenting cells: work considered to be the foundation of much of the recent work on antigen presentation. The work underpins rational T-cell based vaccine design and continues to fuel translational research where discoveries in the areas of antigen discovery, T cell regulation and immunodominance are making a significant impact on new and ongoing cancer immunotherapy trials.

His mechanistic studies have always benefitted from an active interface with the physical sciences,  mathematics and computer science, nanofabrication and engineering.

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.

New form of gift wrap drives male reproductive success

The transfer of complex mixtures of signals and nutrients between individuals is a key step in several biologically important events in our lives, such as breastfeeding and sexual intercourse. However, we know relatively little about the ways in which the molecular gifts involved are packaged to ensure their successful delivery to the recipient.

By studying such events during mating in the fruit fly, researchers at the University of Oxford have identified a new communication mechanism in which nutrients and signals are combined in fatty droplets that stably store their bioactive cargos in males, until they are transferred to females when they dissipate within minutes. These specialised multi-molecular assemblies called microcarriers, are made by the prostate-like accessory gland of the male and contain a central fatty (lipid) core wrapped with multiple proteins, including a molecule called Sex Peptide. When Sex Peptide is released in the mated female, it stimulates her to produce more progeny and reprogrammes her brain so she rejects other male suitors.

Although Sex Peptide is only produced by a limited group of fruit fly species, lipids and lipid droplets are secreted by many glands, including the human prostate and breast. Preliminary work in flies suggests that one of the genes that is essential for the release of microcarriers from secreting cells also plays a critical role in human glands, including the breast. In fact, this regulatory gene is highly expressed in some breast cancers. This suggests that the mechanisms controlling microcarrier formation may be evolutionarily conserved and that microcarriers may play much broader roles in physiological and pathological cell-cell communication, which have yet to be recognised.

This new cell communication mechanism could have implications for breast cancer and understanding its pathology because the regulatory gene essential for driving reproductive success is also expressed in some breast cancers, so if we can better understand the gene’s mechanism, it might be possible to understand how breast cancer can become pathological.

Please see the full article on the Department of Physiology, Anatomy & Genetics website.

The study was a collaboration between the groups of Professor Clive Wilson and Associate Professor Deborah Goberdhan from the Department of Physiology, Anatomy and Genetics, at The University of Oxford. This work has been supported by funding from the Biotechnology and Biological Sciences Research Council (BBSRC), Cancer Research UK, the Wellcome Trust and the Medical Research Council

Paper to be published in PNAS:

Drosophila Sex Peptide Controls the Assembly of Lipid Microcarriers in Seminal Fluid

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

Oxford spin out financed $6.8m for research into oncolytic therapies

Oxford spin out company, Theolytics, has raised $6.8 million in financing from Epidarex Capital and Taiho Ventures, to advance their work into viral derived cancer therapies. The closing of the recent Series A round resulted in participation from existing investor, Oxford Sciences Innovation (OSI) and new involvement from Epidarex Capital and Taiho Ventures LLC.

Theolytics is a biotechnology company founded from the University of Oxford, that harnesses the power of virus research to combat cancer. Originally launched in 2019, the company specialises in oncolytic viral therapy, developing a library of viral variants that can be used to produce new oncolytic viruses that selectively kill certain cancer cells. The in-house library at Theolytics hosts thousands of viral variants upon which researchers can draw candidates for new therapies, akin to phage display libraries used for antibody development.

The company was spun out of Len Seymour’s lab at the University of Oxford with the idea of applying external pressures to viruses to force the emergence of a variant with a set of desired characteristics, such as attacking specific cancers. Their most recent project will focus on ovarian cancer and ‘arming’ viruses with therapeutic agents for a localised, potent expression at the tumour site.

Len Seymour, Co-Founder and Professor of Gene Therapies within the Department of Oncology at the University of Oxford, says:

Bio selection represents a clever strategy to develop therapeutics that exploit scientific mechanisms that are not yet fully understood. By applying the correct selection pressure it is possible to identify oncolytic viruses that could not be designed on the basis of existing knowledge. The most exciting aspects of Theolytics approach are the huge diversity of the viral libraries they have produced using sophisticated molecular shuffling, thereby harnessing the therapeutic power of many diverse adenovirus serotypes, and the clinically relevant model systems they have developed. By combining these two strategic innovations, the Theolytics scientists have developed some truly exciting and world class therapeutic candidates.

In the long run, the company are working to transform the way in which viral therapies for cancer are discovered and developed. Read more about the technology here.