Using Artificial Intelligence and Deep Machine Learning to improve Treatment and Diagnosis of Prostate Cancer

Prof Clare Verrill is a pathologist at the Nuffield Dept of Surgical Sciences, and holds an honorary contract with the Oxford University Hospitals NHS Foundation Trust as a consultant pathologist, specialising in urological pathology. Clare’s primary interests are testis and prostate. Within the ”Verrill Pathology Group” research is focused on digital pathology and image analysis. Clare holds a variety of local and national roles including:  Thames Valley Supraregional Lead for germ cell tumour pathology (since 2011); Chief Investigator of Oxford Radcliffe Biobank (since 2015); RCPath Thames Valley Regional College Advisor (Since June 2017) and Co- lead for Testicular Genomic Clinical Interpretation Partnership (GeCIP) for 100,000 Genomes Project (Genomics England) (since 2015).  She is also the National Cancer Research Institute (NCRI) Cellular Molecular Pathology Initiative (CM-Path) Technology and Informatics Workstream Lead.

By applying Artificial Intelligence (AI) in the cellular pathology setting, Clare and her team hope to deliver benefits for NHS patients in terms of efficiency, accuracy and quality of pathology assessment. Initially, the team hope to develop digital systems that impact clinical care pathways through improving existing workflow efficiency (i.e. potentially reducing turn-around times and making cost savings). In the long term the team hope to develop novel diagnostic strategies relying on machine learning algorithms reliant on tissue morphology features not obvious to a human observer.

One example of Clare’s work is the collaboration with the Finnish Institute of Molecular Medicine (FIMM), which has world leading expertise in digital pathology and image analysis. An image analysis algorithm has been developed, using deep machine learning, which can assess and count tumour infiltrating lymphocytes in testicular germ cell tumours on H&E sections. This helps to avoid the problems of inter-observer variability and subjectivity with pathologist assessment.

Within Oxford Clare collaborates with the Institute of Biomedical Engineering (Prof Jens Rittscher), the Department of Oncology (Prof Andrew Protheroe), the Big Data Institute (Nuffield Department of Medicine) (Dr David Wedge).
National collaborators are Prof Johan de Bono and Dr Clare Turnbull at the Institute of Cancer Research, Dr Matthew J Murray (University of Cambridge), and VisioPharm.

 

Clare’s research is funded by the National Institute of Health Research (NIHR) Oxford Biomedical Research Centre (BRC), CRUK | Oxford Centre, CRUK, Innovate UK.

Combining Radiotherapy, minimally Invasive Surgery and Immunotherapy to enhance Cure Rates in Prostate Cancer

Prof Richard Bryant is an academic urology consultant with a sub-specialist interest in prostate cancer, and a Cancer Research UK funded clinician scientist in the Nuffield Department of Surgical Sciences. His collaborative research group is embedded in the Oxford Institute for Radiation Oncology within the Department of Oncology. He undertook parallel training in urological surgery and laboratory basic science in both Sheffield and Oxford, and has a background training in prostate cancer epigenetics, basic science and translational research. Richard was lead clinician for the Oxford-led VANCE anti-prostate cancer vaccine early phase clinical trial. His research focusses on improving prostate cancer patient outcomes by enhancing cure rates and reducing side-effects.

Richard’s current research aims to address an important unmet clinical need in prostate cancer radiotherapy treatment using pre-clinical models. Whilst radiotherapy with concomitant androgen deprivation therapy is a standard of care for men with prostate cancer, unfortunately not all patients are cured using this approach, and many long term survivors of radiotherapy have a reduced quality of life due to treatment-related sexual, urinary and bowel side effects. The team around Richard is investigating potential synergy by approaches combining radiotherapy with novel minimally invasive surgery focal therapy techniques and immune checkpoint inhibitors. If synergy is observed in these combined treatment models, this would lead to first-in-man early phase clinical trials, with the possibility of improving patient outcomes. The improvement could be achieved through combined use of focal therapy and lower doses of radiotherapy, to avoid either major surgery (which removes the whole prostate gland) or the use of higher dose radiotherapy (which can damage adjacent organs).

Witin Oxford Richard collaborates with the Nuffield Department of Surgical Sciences (including Prof Freddie Hamdy, Prof Ian Mills, Prof Clare Verrill), the Department of Oncology (including Prof Valentine Macualay, Prof Ruth Muschel, Prof Boris Vojnivic), the Oxford Institute for Radiation Oncology (including Prof Geoff Higgins, Sean Smart), and the Weatherall Institute of Molecular Medicine (including Prof Vincenzo Cerundolo).

A further collaborators is Prof Avigdor Scherz at the Weizmann Institute of Science in Rehovot, Israel.

Richards research is funded by CRUK, The Urology Foundation, and UCARE.

Developing Novel Immunotherapy to improve Clinical Efficacy of Prostate Cancer Vaccines

Dr Irina Redchenko is based at the Jenner Institute (within the Nuffield Department of Medicine). Irina completed her PhD in Immunology, and has been researching in the field of cancer immunotherapy for over 15 years in academia and industry, with a focus on trying to improve patient care by developing novel immunotherapies against various cancer types, including prostate cancer.

Prostate cancer has been under investigation as a target for antigen-specific immunotherapies in metastatic disease settings. However, neither of the two clinically most advanced prostate cancer vaccines (Sipuleucel-T and ProstVac) induced strong T-cell immunity. Recently, Irina and her fellow researchers have completed a first-in-human study of two replication-deficient viruses (chimpanzee adenovirus and MVA) targeting an oncofetal self-antigen 5T4 in early stage prostate cancer. Encouraged by the vaccine’s good immunogenicity and excellent safety profile, the team have started the phase I/II trail to test this vaccine in combination with a PD-1 checkpoint inhibitor in the metastatic setting. Until recently, prostate cancer has not been considered amenable to checkpoint blockade drugs. The preliminary results from KEYNOTE-199 study showed an 11% response rate to anti-PD-1 therapy in metastatic castration resistant prostate cancer. The hope is to demonstrate that the Jenner’s experimental vaccine, in combination with anti-PD-1 immunotherapy, will have a significantly higher clinical efficacy than anti-PD-1 treatment as a monotherapy.

Within Oxford Irina is collaborating with the Nuffield Department of Surgical Sciences (including Prof Freddie Hamdy, Prof Richard Bryant, Prof Clare Verrill), the Churchill Hospital, NHS Foundation Trust Oxford University Hospitals (including Dr Mark Tuthill), and the Department of Oncology (including Prof Andrew Protheroe. Furhter collaborators are Prof Silke Gillissen (University of Manchester), Prof James Catto (University of Sheffield), Prof Gert Attard (University College London), Prof Pedro Romero (University of Lausanne).

 

Irina’s research is funded by the FP7 grant of the European Commission.

Prof Freddie Hamdy honoured with Willy Gregoir Medal

During the 34th Annual Congress of the European Association of Urology (#EAU19) Prof Freddie Hamdy has been awarded the prestigious Willy Gregoir Medal, the highest recognition conferred by the Association. The award honours significant contributions to the development of the urological speciality in Europe. The European Association of Urology has been founded in 1973 and represents urological practice, research and education throughout Europe.

Image credits: Alastair Lamb (please click on the image for original Tweet via @LambAlastair)

 

Prof Richard Bryant, who was in the audience at the EAU Opening Ceremony in Barcelona, said: “This is a tremendous honour and achievement for Prof Freddie Hamdy, and reflects his tremendous lifetime contribution to the urology speciality in Europe. It also indicates the amazing influence he has had on so many urology trainees and clinician scientists, both in the UK and across Europe
and beyond, and is extremely well deserved.

 

Freddie is the Chief Investigator of many studies, including the ProtecT (Prostate testing for cancer and Treatment) study of case-finding and randomised controlled trial of treatment effectiveness in prostate cancer – the largest of its kind worldwide. He is also establishing various multidisciplinary research platforms at Oxford and introducing, with colleagues, a new centre for evaluation of minimally invasive technology including robotic surgery.

 

 

Combining International Collaboration and New Technologies to prevent Prostate Cancer

Prof Ruth Travis is a molecular epidemiologist at the Cancer Epidemiology Unit, based at the Nuffield Department of Population Health. Her prior training was in Biological Anthropology and Epidemiology in Cambridge and Oxford. Ruth’s research is ultimately aiming to inform strategies for prostate cancer prevention, by combining the resources of established large cohort studies and international consortia with study designs that take advantage of new technology, both in terms of ‘omics’ and electronic data linkage.

The team around Ruth is investigating a broad panel of potential risk factors, including lifestyle, dietary and biological characteristics, in large populations of men who do and do not go on to develop prostate cancer.  They are particularly interested in hormones and metabolic factors, and their relationships with prostate cancer risk and with modifiable lifestyle and dietary factors. With large study populations and detailed information on prostate cancer tumour characteristics, the focus lays particularly on high risk prostate cancer subtypes.

Ruth is trying to understand what influences risk for developing aggressive prostate cancer, with the ultimate aim of providing population wide guidance on how to best avoid a cancer diagnosis. To date, her team have identified mostly non-modifiable factors are most significant in determining risk of developing cancer (e.g. age, family history and inherited genetic variation). However recent work has indicated that ‘modifiable’ environmental, lifestyle and metabolic risk factors do play a role (including serum concentrations of insulin-like growth factor-1). Ruth’s research is following-up on this lead with comprehensive studies of this metabolic pathway, but also on identifying any other potentially modifiable risk factors.

In Oxford Ruth collaborates with Prof Naomi Allen (Nuffield Department of Population Health, UK Biobank, Prof Freddie Hamdy and Prof Clare Verrill (Nuffield Department of Surgical Sciences). Ruth and her team are leading on the prostate cancer research for a large European cohort study EPIC (European Prospective Investigation into Cancer and Nutrition) including the International Agency for Research on Cancer in Lyon, and EHNBPCCG (Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group). They are also part of several prostate cancer genetics consortia (i.e. PRACTICAL), and collaborate closely with other members, including Dr Rosalind Eeles (ICR, UK) and Prof Chris Haiman (USC, USA).

Ruth’s research is supported CRUK, and the World Cancer Research Fund.

Using Spatial Transcriptomics to support accurate Decision-making in early stage Prostate Cancer

Dr Alastair Lamb is a Clinician Scientist, Senior Fellow in Robotic Surgery and Honorary Consultant Urologist based at the Nuffield Department of Surgery and the Oxford University Hospitals NHS Foundation Trust. He completed his medical training in Oxford and Cambridge, and specialised at the Peter MacCallum Cancer Centre in Melbourne. Alaistair’s research aims to define micrometastatic disease in high risk prostate cancer, focusing on the cancer cells that spread into the lymphatic and blood systems.

Prostate cancer, like other cancers, sheds cells into the lymphatic and blood systems of the pelvis and abdomen and yet little is known about the potential of such cells to form new tumours, nor their genomic status, particularly in high risk ‘localised’ prostate cancer. Understanding these features of an individual’s tumour in more detail will support clinicians in determining differences between different patients tumours and to better tailor treatments accordingly. Alastair and his team aim to discover whether genetic and transcriptomic features of the tumour, the microenvironment and circulating cancer cells correlate with sensitivity to a variety of chemotherapeutic, radiation or surgical treatments. A particular focus of Alastair’s team is to assess spatial heterogeneity in levels of specific transcripts to help identify previously ignored epigenetic phenomena that could give insight into how prostate cancer progresses and responds to treatment.

Within Oxford Alastair collaborates amongst others with the Mark Howarth Laboratory (Department of Biochemistry). Further collaborators are Dr Joakim Lundeberg (SciLifeLab, Universities of Stockholm and Uppsala), Dr Hans Lilja (Memorial Sloan Kettering Cancer Centre, New York), Dr Tamir Chandra (The University of Edinburgh)

Alastair’s work is funded by CRUK, Prostate Cancer UK, the Academy of Medical Sciences, and UCare.

 

Dr David Church awarded with CRUK Advanced Clinician Scientist Fellowship

Dr David Church has recently been awarded a CRUK Advanced Clinician Scientist Fellowship, which supports excellent clinician scientists to develop independence and leadership in their field of academic research.

David’s project aims to define the functional genomic landscape of mismatch repair deficiency (dMMR) and POLE exonuclease domain mutations (POLE-exo*) in colorectal cancer and endometrial cancer, and to determine how variation in these molecular features correlate with patient outcome. By addressing the critical gaps in our understanding of how these factors interact, David hopes to improve care for the large number of patients diagnosed with these cancers, by refining their treatment, and identifying new therapeutic targets.
More than 800,000 people are diagnosed yearly with colorectal (CRC) or endometrial (EC) cancer in Europe and the US. Over 100,000 of these tumours carry a substantially elevated mutational load, usually owing to defective DNA mismatch repair (dMMR), POLE exonuclease domain mutations (POLE-exo*), or in 3–7% cases, unknown causes. These cancers typically display an enhanced T-cell response, and in some contexts, a good prognosis, although the reasons why this association varies are unknown. They are also sensitive to immune checkpoint inhibition; however the determinants of this and the optimum use of these agents is unclear.

David and his team will pool multiple series to generate the largest cohort of hyper/ultramutated CRCs and ECs analysed by genome/exome sequencing to date, and extend their existing preclinical models to provide a detailed assessment of intestinal and endometrial dMMR and POLE-exo* tumorigenesis. The researchers will analyse these in parallel to identify novel drivers and therapeutic targets, and use multispectral immunoprofiling to determine the impact of these variants on the antitumour immune response. They aim to integrate these datasets to understand the basis of the tissue dependency of the association between hyper/ultramutation and prognosis, and identify key prognostic/predictive markers which they will validate in large clinical trial cohorts. They will identify non-dMMR/POLE-exo* hyper/ultramutated cases among the sequenced tumours and investigate their cause using these data and preclinical models, and their consequences using the trial cohorts.

Targeting Prostate Cancer Metabolism in bone metastatic Prostate Cancer

Dr Jessica Whitburn was a NIHR academic clinical research fellow in Urology, and is currently a  Cancer Research UK Oxford Centre DPhil student based at the Botnar Centre for Musculoskeletal Research (within the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences), and has an honorary clinical contract at Oxford University Hospitals. Jessica graduated from University College London and completed her foundation doctor training in London. She completed her basic surgical training in Oxford alongside undertaking laboratory research and completing a post graduate diploma in healthcare research.

Jessica is aiming to improve the effectiveness treatment for patients with metastatic prostate cancer by targeting metabolic features specific to metastatic cancer cells. Prostate cancer is the commonest cancer in men in the UK and the second leading cause of cancer death. Whilst treatment of localised disease is very effective, when it spreads (metastasises), typically to bone, it becomes incurable, and therefore there is an urgent need to find novel treatment strategies for these men. Jessica is working on elucidating how prostate cancer metabolism changes when it spreads to the bone in the hope that by identifying and targeting these changes, it will be possible to develop new treatments. In particular Jessica’s research focusses on an anti-oxidant pathway that cancer cells might use to gain resistance to currently used therapies.

Within Oxford Jessica works with the Prof Claire Edwards and Prof Freddie Hamdy (Nuffield Department of Surgical Sciences). She collaborates with scientists from Keio University, Japan (Prof Soga, Dr Hirayama).

Jessica’s pre-DPhil work was funded by the National Institute of Health Research  Academic Clinical Fellowship programme, her DPhil has been funded by Cancer Research UK, with scholarship funding from the Japanese Society for Promotion of Science.

Enabling more targeted Treatment of Prostate Cancer by de-coding Stress Response Signalling of Cancer Cells

Prof Ian Mills is a molecular biologist with a background in transcriptional regulation and membrane trafficking, based at the Nuffield Department of Surgical Sciences at the John Radcliffe Hospital (Oxford University Hospitals NHS Foundation Trust). He is the John Black Associate Professor of Prostate Cancer and also holds a secondary appointment as Professor of Translational Prostate Cancer Biology at the Centre for Cancer Research and Cell Biology at Queen’s University of Belfast. Ian studied Biochemistry as an undergraduate in Oxford, undertook his PhD training at the University of Liverpool, completed a postdoc at the MRC Laboratory of Molecular Biology in Cambridge, and has been running pre-clinical prostate cancer research groups since 2003.

Due to the high-incidence of prostate cancer relative to the proportion for whom the disease progresses, there is a risk of overtreatment.  By understanding prostate cancer biology Ian and his fellow researchers are aiming to discover molecular signals that will more reliably identify individuals with high-risk of developing lethal disease at the time of diagnosis.  This will enable treatment to be targeted more effectively and reduce treatment of patients without lethal disease, and the associated side effects. In addition disease progression can take a number of years post-diagnosis and there is therefore a time window in which treatments targeting particular molecular properties of the disease can be used to slow or stop progression, if the relevant driving biology is known.  Historically the research in this field is focussed on androgen receptor signalling, but other biological drivers are now known to contribute too.

Ian is studying how metabolic changes in prostate cancer modify the cancer genome, the tumour micro-environment and the stress response signalling of cancer cells to support treatment resistance and disease progression.  He is also working on how inherited/germline genetics impacts on this evolution and developing risk scores with collaborators based on these factors.

The hope is that Ian’s research will help to select patients for early cancer screening and lead to the repurposing of clinically approved metabolic drugs for the treatment of prostate cancer.  If successful, this could ultimately reduce prostate cancer mortality although that would be in the long term.

Within Oxford Ian collaborates with the Nuffield Department of Surgical Sciences (Dr. Alastair Lamb, Prof. Freddie Hamdy, Prof. Richard Bryant), the Target Discovery Unit (within the Nuffield Department of Medicine) (Prof. Jens Rittscher), the Big Data Institute (Dr. David Wedge), and the Nuffield Department of Population Health (Dr. Ruth Travis).

Further collaborators within the UK are Dr. Charlie Massie (University of Cambridge), Prof. Andy Lynch (University of St Andrews), Prof. Ros Eeles (The Institute of Cancer Research), Dr. Zsofia Kote-Jarai (The Institute of Cancer Research), Dr. Simon McDade (Queen’s University Belfast), Dr. Karl Butterworth (Queen’s University Belfast), Dr. Eileen Parkes (Queen’s University Belfast), Dr. Emma Evergren (Queen’s University Belfast), Prof. Richard Martin (University of Bristol), Prof. Silke Gillessen (University of Manchester).

Internationally, Ian collaborates with Dr. Alfonso Urbanucci (Oslo University Hospital), Dr. Harri Itkonen (University of Oslo), Prof. Lisa Butler (University of Adelaide), Prof. Paul Rennie (University of British Columbia), Prof. Massimo Loda (Dana Farber / Harvard Cancer Centre).

Ian’s work is funded by the John Black Charitable Research Foundation, the John Fell Fund, UCARE, the Norwegian Research Council, and the Medical Research Council.

 

Using Big Data to understand Biological Pathways of Prostate Cancer Risk Development

Prof Tim Key is an Epidemiologist based at the Cancer Epidemiology Unit (within the Nuffield Department of Population Health). He originally trained and practised as a veterinary surgeon, before taking up further training in nutrition and epidemiology. Tim’s research is trying to establish an understanding of the aetiology (causes) of prostate cancer, with the aim of identifying modifiable factors which can be changed and therefore reduce the risk for developing this disease. The research team is particularly focused on understanding the causes of the more aggressive forms of prostate cancer.

The aim is to provide the evidence needed to develop approaches to reducing prostate cancer risk, for example by advice on diet by studying large data sets gathered from UK wide population studies, as well as from international collaborative projects. Some of the best known risk factors for prostate cancer are increasing age, ethnic background, family history and certain genetic factors, but none of these can be changed. The team around Tim has found that a growth factor in the blood (called IGF-I) is positively related to risk of prostate cancer, and a much of their current research is aimed at understanding the broader aspects of this biological pathway and whether it is modified by factors such as diet and body fatness. The researchers are also systematically examining other factors which might affect the risk for developing aggressive prostate cancer, including hormones and nutritional status.

Within Oxford Tim is collaborating with a wide range of epidemiologists, clinicians and biochemists. This includes the Nuffield Department of Population Health (Prof Ruth Travis, Prof Naomi Allen), the Department of Oncology (Prof Valentine Macaulay) and the Nuffield Department of Surgical Sciences (Prof Freddie Hamdy, Prof Hans Lilja). Further collaborators are Prof Richard Martin (University of Bristol) and within the two international consortia Oxford is leading on: EPIC (European Prospective Investigation into Cancer and Nutrition) and EHNBPCCG (Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group).

Tim’s research is funded by CRUK and the World Cancer Research fund.