New network Oxford Cancer launches

Today Oxford Cancer launches at the University of Oxford – a new pan-divisional research theme that has been established to support researchers across the city of Oxford in solving the key challenges in cancer research. Through this network, Oxford is tackling the biggest questions and highlights Oxford’s commitment to cancer as one of its strategic research themes.

Cancer remains the second leading cause of death worldwide, with an estimated 10 million cancer mortalities in 2020 alone. It continues to be a barrier to increasing life expectancy in every country of the world.

Oxford has over 900 cancer researchers based across the University and Hospitals Foundation Trust, with academic strengths in a wide variety of areas, including immunology, data science, cell biology, physical science & drug development. Bringing together this expertise is what Oxford Cancer aims to do, in order to facilitate multi-disciplinary research across its partners. It ultimately aims to solve the key challenges cancer represents through developing and delivering novel strategies for early detection and curative treatment of a range of different cancer types. This approach will be informed by the latest fundamental scientific discoveries and underpinned by world leading data science and technological developments that are unique to Oxford.

Read the full story here.

The next step in personalised cancer medicine

Researchers at the Botnar Research Centre, University of Oxford have developed technology that facilitates standalone long-read Oxford Nanopore sequencing of single cells. This breakthrough technology has the potential to open new avenues within genomics and enable future discoveries to understand the causes of many human diseases.

The work, in part supported by grants from the UKRI (Innovate UK, EPSRC and MRC), results from a collaboration with researchers from the Department of Chemistry at Oxford University, ATDBio, a world leader in complex oligonucleotide chemistry, and pharmaceutical company BristolMyersSquibbs. The study has been published in this week’s issue of Nature Biotechnology.

“The application of accurate long-read single-cell sequencing will have a transformative effect on the wider single-cell sequencing community, as longer and full-length transcriptomic sequencing allows users to capture more information about the transcriptional and functional state of a cell,” says Assistant Professor Adam Cribbs, senior author of the paper and Group Leader in Systems Biology and Next Generation Sequencing Analysis at the Botnar Research Centre. “This means that we move closer to being able to better understand and diagnose diseases such as cancer”.

Single-cell genomics, the ability to examine all information contained in an individual cell, is a rapidly evolving field and is dominated by droplet-based short-read single-cell sequencing applications. In this approach, cells are encapsulated with barcoded RNA-capture microbeads into droplets within an oil emulsion. Each droplet becomes a discrete reaction vessel, associating a different barcode with each cell’s RNA and a unique molecular identifier (UMI) with each RNA transcript.  Once barcoded, RNA from all cells can be pooled and processed conventionally for next generation sequencing.  During sequencing, both the original RNA sequence and the associated barcode and UMI are determined. Key to measuring abundance of each RNA and correctly associating them with their cell of origin is accurate assignment of the UMIs and barcodes.

Long-read sequencing approaches, such as those of Oxford Nanopore Technologies, are currently revolutionising bulk sequencing approaches. “Long-read single-cell technology has the potential to interrogate not only RNA abundance, but also splice variants, structural variation and chimeric transcripts at the single-cell level. Collectively, the ability to determine these features accurately will improve diagnostics and biological understanding. However, Nanopore sequencing can be inaccurate, which hinders the critical steps of barcode and UMI assignment, making its application to single-cell sequencing challenging,” explains Dr Martin Philpott, first author of the paper and Director of the Next-Generation sequencing facility at the Botnar Research Centre.

To overcome these challenges, the team has developed a new approach called single-cell corrected long-read sequencing (scCOLOR-seq) that identifies and corrects errors in the barcode and UMI sequences, permitting standalone cDNA Nanopore sequencing of single cells. “Each mRNA molecule is tagged with a short sequence which identifies it within a certain droplet,” adds Dr Cribbs. “However, Nanopore long-read sequencing is too error prone to reliably sequence these tags, making it difficult to map the mRNA back to its specific cell. What we’ve been able to do is to develop a practical method for building redundancy into the tag, allowing inaccuracies within the sequencing to be pinpointed, and then correct them. The mRNA can then be linked back to an individual cell.”

The research was developed in collaboration with ATDBio, an Oxford/Southampton based company, created by Professor Tom Brown Sr at the Chemistry Department, University of Oxford. Dr Tom Brown Jnr, Chief Scientific Officer of ATDBio, says, “The new scCOLOR-seq method is the first of many innovations resulting from our collaboration with the Botnar Research Centre team. The collaboration has been one of our most interesting and successful, and we are pleased to see our work recognised in Nature Biotechnology. It’s a great example of how we at ATDBio can apply our expert knowledge of nucleic acid chemistry and complex oligonucleotide synthesis to difficult problems in biology and beyond, together with our corporate and academic partners”.

“This study demonstrates an incredible cross-disciplinary team effort to advance single-cell technologies and is the result of strategic investments into these technologies at our department,” adds Professor Udo Oppermann, Director of Laboratory Sciences at the Botnar Research Centre and co-senior author of the paper. “We will continue our collaborative efforts to develop innovative single-cell approaches and – as demonstrated in the paper- apply this to molecular analyses in primary and secondary bone and other haematological cancers. Our intention is to advance these technologies in personalised medicine approaches such as cancer diagnosis allowing rational clinical decision making.”

Ludwig Oxford and Oxford University welcome Professor Stefan Constantinescu

Oxford’s cancer community is delighted to welcome Professor Stefan Constantinescu, a physician scientist and authority on the signalling pathways and molecular mechanisms of blood cancers, especially myeloproliferative neoplasms, a collection of slow growing blood cancers that can progress to acute malignancies. He is a member of the Ludwig Institute for Cancer Research, Professor of Cell Biology at the Université catholique de Louvain, Director of Research (Honorary) at the Fonds National de la Recherche Scientifique (FRS-FNRS), Belgium and President of the Federation of European Academies of Medicine (FEAM). Constantinescu will spend 25% of his time at the Ludwig Oxford Branch and the remainder of the time at his existing Ludwig laboratory in Brussels.

Constantinescu has received many honors for his work, including membership of the Royal Academy of Medicine of Belgium and the Belgian Government prize for basic medical sciences. He is internationally known for his groundbreaking contributions to our understanding of the mutations and mechanisms that drive myeloproliferative disorders. In a fruitful collaboration with William Vainchenker, he discovered that a mutation (V617F) in a signalling enzyme named Janus kinase 2 (JAK2) occurs in most patients with polycythemia vera, in which red blood cells accumulate abnormally. Constantinescu’s subsequent work demonstrated how this mutation causes disease, leading to the development of novel therapies to treat myeloproliferative disorders and the widespread clinical use of genetic tests to detect the mutation.

Constantinescu has also identified and characterised other common mutations in the thrombopoietin receptor that cause these blood disorders. He has further demonstrated that mutated calreticulins –“chaperone” proteins that otherwise help fold other proteins appropriately—can induce myeloproliferative disorders via abnormal activation of the thrombopoietin receptor, identifying a novel oncogenic mechanism. His discoveries have helped transform the field and continue to open new avenues for the development of targeted therapies.

Constantinescu’s Ludwig Oxford lab will focus on a systematic study of signalling and epigenetic regulation during oncogenesis in chronic myeloid cancers and their progression to the severe condition, secondary acute myeloid leukaemia. Ludwig Oxford’s research programme will be enhanced by Constantinescu’s presence, and his own research programme will benefit from Ludwig Oxford’s expertise in cancer epigenetics, represented by the laboratories of Yang Shi, Chunxiao Song, Skirmantas Kriaucionis and Benjamin Schuster-Böckler.

Read more about the new Constantinescu research group here.

Study investigating targeted drug delivery by focused ultrasound for pancreatic cancer opens

University of Oxford researchers have begun recruitment to a study looking at whether chemotherapy medication can reach pancreatic tumours more effectively if encapsulated within a heat-sensitive shell and triggered with focused ultrasound.

The Phase I PanDox study, which is supported by the NIHR Oxford Biomedical Research Centre (BRC), aims to learn if using thermosensitive liposomal doxorubicin and focused ultrasound (FUS) results in enhanced uptake of doxorubicin in pancreatic tumours, compared to doxorubicin alone.

PanDox is being carried out as a multi-disciplinary collaboration between the Oxford University Institute of Biomedical Engineering, the Oncology Clinical Trials Office (OCTO),  Oxford University Hospitals (OUH) NHS Foundation Trust and Celsion corporation, the manufacturer of the proprietary heat-activated liposomal encapsulation of doxorubicin ThermoDox used in the study.

The Oxford BRC’s Co-theme Lead for Cancer, Prof Mark Middleton, Head of the university’s Department of Oncology at is the chief clinical investigator on the trial. Prof Constantin Coussios, Director of the Institute of Biomedical Engineering, is the lead scientific investigator.

The trial will recruit 18 patients; ThermoDox will be administered intravenously in 12 patients with a pancreatic ductal adenocarcinoma tumour that cannot be removed with surgery; the drug will then be released by gentle heating produced by focused ultrasound outside the body. This will be compared to conventional systemic delivery of doxorubicin without FUS in the other six patients.

As well as assessing whether uptake of doxorubicin is improved with FUS, the team will compare how the tumour responds to the treatment, examine the impact on patient symptoms and assess the safety of the treatment.

The study, which is expected to be completed by December 2022, is similar in design to Oxford’s 10-patient TARDOX study, which demonstrated that ThermoDox plus focused ultrasound increased doxorubicin tumour concentrations by up to 10-fold and enhanced nuclear drug uptake in patients with liver tumours. The findings were published in Lancet Oncology.

The lead oncology clinical research fellow on the PanDox study, Dr Laura Spiers of OUH, said: “Pancreatic cancer has a low five-year survival rate of approximately 10% and drug-based treatments remain less effective than in other cancers, in part due to the unique challenges presented by the stroma surrounding pancreatic tumours.

“Therefore, finding innovative and effective means of delivering high concentrations of anti-cancer agents such as doxorubicin may lead to a breakthrough for this difficult-to- treat cancer.”

Dr Michael Gray, lead biomedical engineering research fellow, said: “Based on the patient-specific treatment planning approaches developed and validated during the TARDOX trial, PanDox will deliver focused ultrasound mild hyperthermia without either MR-based or invasive thermometry. The ultimate goal is to develop a cost-effective and scalable approach that can be rapidly deployed for the benefit of pancreatic patients.”

14 new CRUK Oxford Centre Development Fund Awardees

The CRUK Oxford Centre are pleased to announce the 14 projects that have been selected to receive pump-priming funds. This unique scheme aims to support collaborative projects in cancer research which are a key area of activity for the Centre.

Please see a summary of the awardees and their projects below.

Tom Agnew, Sir William Dunn School of Pathology

ARH3 as a potential new biomarker in breast, ovarian and pancreatic and prostate cancer

To protect the genome from damage, organisms have evolved a cellular defence mechanism termed the DNA damage response. Exploiting DDR pathways to specifically target and kill cancer cells has become an attractive therapeutic avenue of cancer research. This is exemplified by the synthetic lethal interaction between PARP inhibition and BRCA1 or BRCA2-deficient tumours. PARP inhibitor drug resistance is a major issue for treating these cancers. This project will investigate the ARH3 enzyme as a target of reversing this resistance.

 

Elizabeth Mann et al., The Kennedy Institute of Rheumatology, NDORMS

Ex vivo phenotyping of Th17 cells from colorectal cancer patients

Although the immune system is critical in protecting against cancer development, inflammation can worsen disease. Impairing Th17 cells, a subset of CD4+ T cells, reduces tumour burden in mouse models of colorectal cancer (CRC) indicating that Th17 signalling may have novel biomarker and/or therapeutic utility. This project will investigate if Th17 cells are different in number and phenotype in clinically-relevant subclasses of CRC tumours – thus making them potential biomarkers

 

Kourosh Honarmand Ebrahimi & James McCullagh, Department of Chemistry, Chemistry Research Laboratory

Metabolomics investigation of an emerging immunometabolic pathway linking viral infection and inflammation to cancer

The activity of the antiviral enzyme radical S-adenosylmethionine (SAM) containing domain 2 (RSAD2) (also known as viperin) plays a key immunometabolic role in supporting immune function to fight a wide range of viruses. In tumour microenvironment, this activity could support tumorigenesis and tumour development via different mechanisms. In this project, the team will use a variety of analytical methods, including metabolomics and 13C tracer studies, to investigate how the immunometabolic function of RSAD2 supports cancer cell proliferation.

 

Linna Zhou, The Ludwig Institute & Department of Chemistry

Engineered gastrointestinal tissues to investigate the influence of enteric neurons in cancer progression

It has been increasingly recognised that the interactions between neurons and cancer cells, and neurons and immune cells, are important in cancer initiation, progression and metastasis. This project will use an engineering approach to generate 3D GI tissues with naturalistic cellular architecture to recapitulate the interactions of enteric neurons, immune cells and epithelial cells during cancer development. This is to assess how cancer cells migrate along neurons and how neuro-immune interactions shape the tumour microenvironment to facilitate the growth and migration of cancer cells.

 

Mariolina Salio & Graham Collins, Human Immunology Unit & Department of Haematology, Oxford University Hospitals

Immune microenvironment signatures predictive of response in patients with classical Hodgkin Lymphoma treated with checkpoint inhibitors

A major goal in the treatment of classical Hodgkin Lymphoma (cHL) is to reduce the burden of chemotherapy and radiotherapy with its associated short- and long-term toxicities, whilst maintaining high rates of cure. PD1/PD-L1 inhibitors are associated with high response rates. In solid tumours, the mechanism of action of PD1/PD-L1 inhibitors is believed to be mediated by enhanced activation of tumour specific CD8+ T cells. In cHL few CD8+ T cells are present in the tumour microenvironment, so the mechanism of action of PD1 inhibitors in this disease is still unclear. This project will investigate changes in the tumour microenvironment in biopsy material from patients with cHL treated with PD1/PD-L1 inhibitors, to identify signatures which might correlate with the therapeutic effect of these drugs.

 

Karthik Ramasamy & Ross Sadler, Department of Haematology, Oxford University Hospitals & Nuffield Department of Medicine

Post translational modification of free light chains as a biomarker for progression from monoclonal gammopathy of undetermined significance to myeloma

A pilot study to characterise post translational modifications of serum free light chains in both patients with MGUS and myeloma. A full summary of this project can be found here.

 

Monica Olcina et al., MRC Oxford Institute for Radiation Oncology, Department of Oncology

C5aR1 as a biomarker in ovarian cancer – Towards the development of radioligands for imaging and therapy of C5aR1 expressing tumours 

This project will assess C5aR1 as a biomarker to support the development of radioligands for molecular imaging and therapy of C5aR1 expressing tumours. Emerging evidence indicates that C5aR1 signalling stimulates ovarian cancer growth through regulation of oncogenic PI3K/AKT signalling. This project is investigating C5aR1 expression in a range of human ovarian cancer and healthy tissues and will also establish C5aR1 overexpression and knockdown cell lines to be used as tools in the development of radioligands (synthesised by collaborators). In the future, these radioligands will be preclinically tested for selective targeting and visualisation of C5aR1-expressing tumours – with ultimate testing in future clinical trials.

 

Ricardo Fernandes, Nuffield Department of Medicine

Development of a new approach to target FLT3 signalling in AML

This project will develop protein molecules to reduce signalling by the FLT3 receptor in myeloid cells. Acute myeloid leukaemia (AML) is the most common form of acute leukaemia in adults, and approximately a third of patients with AML present a heterogeneous group of activating FLT3 gene mutations. Enhanced FLT3 activity contributes to abnormal proliferation and differentiation of myeloid cells. Despite representing an attractive therapeutic target, small molecule inhibitors of FLT3 have achieved mixed results in clinical trials, partly driven by the diversity of FLT3 gene mutations and escape variants. This project will investigate a new approach for suppressing receptor signalling.

 

Simon Carr & Wojciech Barczak, Department of Oncology

Tumour specific neo-antigens derived from the non-coding genome

Cancers use a diverse array of mechanisms to evade the immune system such as down-regulating immune checkpoint pathways, and the development of therapeutic antibodies targeting immune checkpoints (such as anti-PD1 and CTLA4) represents one of the most important breakthroughs in cancer therapy. This project will look at the contribution of the non-coding genome to the tumour antigen landscape. It will use a novel method to manipulate the antigen landscape on tumour cells, by blocking PRMT5 activity, which we have shown to be important in regulating the expression of a proportion of the non-coding genome.

 

Andrew Blackford, Department of Oncology

Characterising short linear peptide motifs in tumour suppressor proteins 

Some tumour suppressor genes that are most commonly found to be mutated in patients with a hereditary predisposition to cancer are involved in repairing DNA damage in cells. However, we still do not understand exactly how many DNA repair proteins work at the molecular level, how drug resistance can develop in DNA repair-deficient tumours, nor why mutations in the intrinsically disordered regions of these proteins outside their known protein domains can predispose to cancer.

There is thus an urgent need to do more basic research into how DNA repair proteins function at the molecular level in order to understand potential drug resistance mechanisms as well as identify additional drug targets when resistance to radiotherapy and chemotherapy develops. The aim of this project is to identify novel protein interactors for the highly evolutionarily conserved but as-yet uncharacterized short linear peptide motifs in DNA repair proteins.

 

Thomas Lanyon-Hogg, Department of Pharmacology

Development of novel Hedgehog acyltransferase inhibitors from HTS hits to lead series

Hedgehog (Hh) signalling drives growth and is activated in several cancers. Hedgehog acyltransferase (HHAT) activity is required for Hh signalling, making HHAT an attractive target for inhibition. This project will build on the labs existing success in order to develop the most potent HHAT inhibitors to-date.

 

Val Macaulay, Ian Mills & Jack Mills, Department of Oncology & Nuffield Department of Surgical Sciences

Investigating nuclear IGF-1R function in clinical prostate cancers

 Insulin-like growth factors (IGFs) play key roles in prostate cancer biology. Type 1 IGF receptors (IGF-1Rs) are up-regulated in primary cancer and associated with lethal castrate-resistant prostate cancer (CRPC). This project aims to understand how nuclear IGF-1R regulates expression of genes contributing to cancer cell growth, androgen response and therapy resistance in vivo.

 

Wayne Paes et al., Centre for Cellular and Molecular Physiology, Nuffield Department of Medicine

Empirical determination of molecular biomarkers for precision-based immunotherapy in colorectal cancer

 Immune checkpoint inhibitors (ICIs) are only efficacious in ~15% of CRC patients while tumours in ~85% of patients remain innately resistant to ICI therapy. This pilot study aims to identify and correlate novel biomarkers in Immune Checkpoint Inhibitor (ICI)-sensitive and ICI-refractory colorectal cancer subsets at multiple levels. Characterisation of subsets will allow for identification of which are most responsive to ICIs and identify new potential therapeutic targets for those that are not.

 

Shijie Cai et al., Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine

Identification of small molecule inhibitors and synthetic lethality for GTP cyclohydrolase in triple-negative breast cancer

Triple-negative breast cancer (TNBC) accounts for about 10-15% of all breast cancer, with over 8000 cases diagnosed every year in the UK and estimated 1.7 million new cases worldwide. TNBC differs from other types of breast cancer in that they grow and spread faster. Chemotherapy is still the mainstay therapeutic option; however, patients suffer a high rate of distant recurrence and death. Thus, there is an unmet need to develop new small molecule inhibitors for TNBC therapy. GTPCH is a recently identified protein that drives TNBC growth. This project will identify small molecule inhibitors and synthetic lethal genes for GTPCH and enable the researchers to develop new inhibitors targeting TNBC.

Dr Lennard Lee awarded ACP McElwain Prize for contributions to medical oncology

Dr Lennard Lee, Academic Clinical Lecturer at the University of Oxford, has been awarded the 2020 Association of Cancer Physicians (ACP) McElwain Prize for his contribution to the development of Medical Oncology in the UK.

During the COVID-19 pandemic, Dr Lee’s contributions were best reflected in his creation and implementation of a national prospective observational cohort study of cancer patients during the COVID-19 pandemic, the UK Coronavirus Cancer Monitoring Project (UK CCMP). This was one of the largest global registries and the first to identify that cancer treatments can be safely delivered during a COVID-19 pandemic.

The initial phase of the project has been successfully achieved with the roll out and implementation of the UK CCMP emergency observational response network, as well as studies to determine those in our population who are most at risk – such as blood cancer patients.

Thanks to this project, the UK oncology community now has the tools and the mechanism to learn from each case of COVID-19 in cancer patients and the evidence required to bring about clinical management/service/treatment decision changes to improve the outcomes of cancer patients. The data from this project has helped form the guidelines which have been published from NHS England about the resumption of cancer services and led to the return of near-normal chemotherapy prescribing levels.

Building on the success of this work, Lennard is now leading on further studies to understand and better safeguard cancer patients during the pandemic. He has co-launched projects on COVID-19 vaccine efficacy, understanding how this is impacted by cancer treatments, and studies to identify other effective COVID-19 risk reduction interventions.

Lennard Lee said

“I am honoured to receive this award on behalf of all the clinicians and researchers who took part in the UKCCMP. The work by the UK oncology community had global impact, demonstrating that cancer patients can be treated safely during the pandemic. No one should be denied appropriate cancer treatments and it is important that we continue to deliver research excellence in order to protect the vulnerable during this pandemic”.

For more information about the UK CCMP see here.

Two clinical academic research partnerships awarded to Oxford researchers

Dr Karthik Ramasamy and Dr John Jacob are both Oxford clinical researchers that have been awarded a Clinical Academic Research Partnership (CARP) by the MRC. Both have been awarded upwards of £200,000 to fund projects investigating myeloma early detection & brain cancer modelling, respectively. Find out more about the projects being funded with this award below.

Dr Karthik Ramasamy

Earlier diagnosis of the bone marrow cancer myeloma is a high priority for patients since it can both improve survival and allow for better control of symptoms. Every case of myeloma is preceded by a condition called Monoclonal Gammopathy of Undetermined Significance (MGUS) and individuals with MGUS are regularly monitored so that progression to myeloma can be caught early.

While this approach is benefitting some patients, there are two main issues that still need to be overcome to improve earlier myeloma diagnosis:

  1. MGUS is largely symptomless and often undiagnosed, meaning that 80-90% of myeloma patients are diagnosed without first receiving an MGUS diagnosis that would have prompted monitoring for myeloma.
  2. Only 1% of patients with MGUS progress to myeloma every year and the risk of progression is not well defined, placing a large resource burden for monitoring on healthcare providers and creating anxiety for patients.

In this MRC CARP award, Dr Karthik Ramasamy will address both of these challenges. Firstly, working with Professor Kassim Javaid, Professor Daniel Prieto-Alhambra, Dr Constantinos Koshiaris and data from primary care health records, Dr Ramasamy will identify specific clinical signs/symptom clusters associated with MGUS to enable a greater proportion of individuals with MGUS to be diagnosed and monitored. Secondly, additionally collaborating with Dr Ross Sadler, Professor Chris Schofield and Professor James McCullagh, Dr Ramasamy will seek to identify routinely recorded clinical characteristics and additional protein biomarkers that improve prediction of progression from MGUS to myeloma in a cohort of patients undergoing monitoring at Oxford University Hospitals NHS Trust. This latter work is bolstered by a recently awarded CRUK Oxford Centre Development Fund award, which will enable the research team additionally to pilot protein glycosylation analysis in blood samples collected as part of a current study investigating serological markers in plasma cell dyscrasias (BLOOM).

Dr Karthik Ramasamy is Lead Clinician for myeloma and other plasma dyscrasias in Thames Valley Strategic Clinical Network and Divisional Lead of Cancer Research across Thames Valley and South Midlands Research Network.

Learn more about myeloma early detection research in Oxford.

Dr John Jacob

Brain cells that originate in the cerebellum give rise to the most common childhood brain tumour, known as medulloblastoma, which can also affect adults. Although it can be cured, it is often a devastating disease, with common treatment options resulting in an increased risk of adverse side effects such as strokes and seizures.

Like most cancers, the development of new treatment options that improve survival rate and reduce side effects is reliant on researchers establishing models that reflect the human tumours, in order to test the efficacy of new therapeutics before these are tested in patients. Existing models for medulloblastoma have shortcomings making the discovery of new treatment options slow. This is due to:

  1. Growing medulloblastoma cells outside of a patient is hard, due to the change in environmental factors. Growing cells outside the body usually does not accurately reflect the microenvironment that cells are derived from, and so the cells will behave differently and unlike a real tumour. As a result, only a few cell lines from medulloblastoma patients have been successfully grown ex vivo.
  2. Models can be costly, and these include mouse-based models, which pose limitations due to the difference in species
  3. Medullobastoma tumours are genetically different between patients – there is no ‘one size fits all’ model and there is a need to develop more treatment options that target specific genetic subtypes in order to improve survival.

In this CARP award, Dr John Jacob (Nuffield Department of Clinical Neurosciences) aims to investigate a specific genetic subtype of medulloblastoma (known as sonic hedgehog medulloblastoma) – and test if the presence of the tumour microenvironment, which consists of non-cancerous cerebellar tissue, is necessary to better simulate the typical tumour growth conditions.

Working alongside Associate Professor Esther Becker (Nuffield Department of Clinical Neurosciences) and Dr Benjamin Schuster-Boeckler (Big Data Institute & Oxford Ludwig Cancer Institute), the team hope to recreate the in vivo tumour microenvironment more accurately compared to existing models. The Becker group previously established a methodology to grow human cerebellar neurons from human induced pluripotent stem cells (hiPSC). By using hiPSCs to form miniature cerebellar structures, termed cerebellar organoids, the tumour microenvironment can be recreated in a dish.

The team hope to overcome the existing modelling difficulties by growing medulloblastoma cells on these organoids. Dr Jacob, aided by the computational biology expertise of Dr Schuster-Boeckler will then investigate the growth of individual tumour cells, in a more physiological context. The resulting outcomes could mean the development of a new model to test patient-specific therapies on, in order to assess their toxicities and efficacy more accurately.

Dr John Jacob is a consultant neurologist who is interested in better understanding the genetic complexity of cancer and what it means for personalised treatment. Through this award and collaboration, Dr Jacob hopes to improve the success of therapy development and ultimately improve the repertoire of therapies of this cancer.

The Medical Research Council Clinical Academic Research Partnership scheme allows NHS consultants with a PhD or MD to participate in collaborative high-quality research partnerships with established leading biomedical researchers.

 

Potential for radiotherapy and VTP multimodality therapy for prostate cancer

Each year in the UK around 48,500 men are diagnosed with prostate cancer, and 11,900 die from this malignancy. The most common radical treatments for prostate cancer are surgical removal of the prostate gland (prostatectomy), or radiotherapy (usually combined with hormone treatment).

However, there is a need to improve the overall patient outcomes from radical treatment, as many cases of high-risk prostate cancer recur. Moreover, there is an unmet clinical need to reduce radical treatment side effects.

Vascular targeted photodynamic therapy (VTP) is a novel minimally invasive precision surgery technique that has been developed to focally treat prostate cancer. VTP destroys the vasculature supply of blood to the tumour, thereby providing tumour control.

To date, VTP has been investigated in clinical trials as a monotherapy for low-volume, low-risk prostate cancer. Whilst VTP has been combined with other treatments such as hormone therapy in pre-clinical models, to date it has not been investigated alongside external beam radiotherapy to assess the effects of combined treatment on prostate cancer tumour control.

A recent study from Richard Bryant and Freddie Hamdy of the Nuffield Department of Surgical Sciences, alongside collaborators in the Institute of Biomedical Engineering & Department of Oncology, and collaborators from the Weizmann Institute of Science (Israel) and the National Cancer Institute (National Institutes of Health, USA), has investigated the impact of combining VTP with external beam radiotherapy treatment, and the potential improvement to treatment outcomes.

In a recent publication in the British Journal of Cancer, the team used a multi-modality treatment approach to test the sequential combination of fractionated radiotherapy and VTP – which have previously not been used together.

They found that, whilst fractionated radiotherapy or VTP alone can help delay tumour growth, combination therapy using fractionated radiotherapy followed by VTP suppressed tumour growth to a greater extent than either treatment alone. Radiotherapy induced changes to the blood vessels within the tumour, which may be a contributing factor to the increased effectiveness of subsequent VTP as part of combination therapy. Ongoing studies are now investigating the immunological effects of the combined treatment.

This is the first time that VTP has been evaluated in combination with external beam radiotherapy treatment, either for prostate cancer or any other solid-organ tumour. This pre-clinical study provides the proof-of-concept necessary to go on and test this multi-modality approach in first-in-man early phase clinical trials. Following future testing of safety and efficacy in patients, this combined radiotherapy and VTP approach could help to redefine best practice for treating certain prostate cancer patients in a more effective way.

About the study

This study was a collaboration between Richard Bryant (Nuffield Department of Surgical Sciences), Freddie Hamdy (Nuffield Department of Surgical Sciences), Ruth Muschel (Department of Oncology) and Avigdor Scherz (The Weizmann Institute of Science, Israel). It was funded by a Cancer Research UK & Royal College of Surgeons of England Clinician Scientist Fellowship (reference C39297/A22748) and by a research grant from The Urology Foundation.

AI endoscopy enables 3D surface measurements of pre-cancerous conditions in oesophagus

Clinicians and engineers in Oxford have begun using artificial intelligence alongside endoscopy to get more accurate readings of the pre-cancerous condition Barrett’s oesophagus and so determine patients most at risk of developing cancer.

In a research paper published in the journal Gastroenterology, the researchers said the new AI-driven 3D reconstruction of Barrett’s oesophagus achieved 97.2 % accuracy in measuring the extent of this pre-cancerous condition in the oesophagus in real time, which would enable clinicians to assess the risk, the best surveillance interval and the response to treatment more quickly and confidently.

Barrett’s is a pre-malignant condition that develops in the lower oesophagus in response to acid reflux. There is a less than 0.1-0.4% risk per year of developing cancer with normal Barrett’s oesophagus – or one in 200 patients. However, that risk increases with the extent of Barrett’s lining.

Clinicians use a system called the Prague C&M criteria to give a standardised measure of Barrett’s oesophagus. This uses the circumferential length of the Barrett’s section and the maximum extent of the affected area. This score roughly determines the level of risk of developing cancer and how often the patient needs to be surveyed by an endoscopist, usually every five years for low-risk cases and two to three years for longer Barrett’s segments.

Oxford University Hospitals (OUH) NHS Foundation Trust has a cohort of around 800 patients with Barrett’s who have periodic endoscopic surveillance.

OUH Consultant Gastroenterologist Professor Barbara Braden, together with Dr Adam Bailey, oversees a large endoscopic surveillance programme for Barrett’s patients at OUH. She says the quality of the endoscopy is very dependent on the skill and expertise of the person carrying out the procedure.

“Until now, we have not had any accurate ways of measuring and quantifying the Barrett’s oesophagus. Currently, we insert the scope and then we estimate the length by pulling it back,” said Prof Braden.

“We asked colleagues from the Department of Engineering Science – Prof Jens Rittscher and Dr Sharib Ali – whether they could find a way to measure distances and areas from endoscopic videos to give us a more accurate picture of the Barrett’s area and they came up with the brilliant idea of three-dimensional surface reconstruction.”

Prof Braden, of the University of Oxford’s Translational Gastroenterology Unit, based at the John Radcliffe Hospital, added:

“Currently, you have to have a great deal of experience to know how to spot the subtle changes which indicate early neoplastic alterations in Barrett’s oesophagus. Most endoscopists don’t encounter an early Barrett’s cancer that often. So, instead of teaching thousands of endoscopists, by applying deep learning techniques to endoscopic videos you can teach a programme.”

The Oxford study is using technology to reconstruct the surface of the Barrett’s area in 3D from the endoscopy video, giving a C&M score automatically. This 3D reconstruction allows the clinician to quantify precisely the Barrett’s area including patches or ‘islands’ not connected to the main Barrett’s area.

Dr Sharib Ali, the first author of the paper and the main contributor of this innovative technology, is part of the team working on AI solutions for endoscopy at the University of Oxford’s Department of Engineering Science. He said:

“Automated segmentation of these Barrett’s areas and projecting them in 3D allows the clinician to not only report very accurately the extent of the Barrett’s area, but to pinpoint precisely the location of any dysplasia or tumour, which has not been possible up to now.”

The technique was tested on a purpose-built 3D printed oesophagus phantom and high-definition videos from 131 patients scored by expert endoscopists. The endoscopic phantom video data demonstrated a 97.2 % accuracy for the C&M score measuring the length, while the measurements for the whole Barrett’s oesophagus area achieved nearly 98.4 % accuracy. On patient data, the automated C&M measurements corresponded with the endoscopy expert scores.

“With this new AI technology, the reporting system will be much more rigorous and accurate than before. It makes it much easier when the clinician sees the patient again – they know exactly where to target biopsies or therapy. And the quicker and more efficient it is, the better the experience for the patient,” Dr Sharib Ali explained.

The research was supported by the NIHR Oxford Biomedical Research Centre (BRC), through its cancer and imaging themes.