Identifying Novel Therapeutic Targets and Treatments for Colorectal Cancer

Dr Elizabeth Mann is a postdoctoral researcher in Fiona Powrie’s muscosal immunology group, based at the Kennedy Institute of Rheumatology (within the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences). Beth did her Master’s and PhD in Immunology in the MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, based at King’s College London.

Beth and her fellow researchers are interested in novel approaches to treat colorectal cancer, focussing on treatment-refractory patients. In particular, they are looking to better understand the intricate roles of the immune system and microbiome in cancer so that we can target these to improve treatment. Humans are colonised by an ecological community of microorganisms that outnumber host cells and are highly enriched in the gut. Normally, these commensals have a symbiotic relationship with the host, but there is growing evidence that changes to its composition may be a causing factor for many diseases, including cancer, making the microbiome a potential therapeutic target. The hope is that Beth’s work will identify novel therapeutic targets and treatments that, importantly, will be beneficial for those patients who current treatment options offer little curative potential.

One aspect of Beth’s project funded by CRUK is part of an international collaboration, which aims to manipulate the microbiome to beat colorectal cancer, called OPTIMISTICC (OPportunity To Investigate the Microbiome’s Impact on Science and Treatment In Colorectal). As part of this consortium the role of the Oxford team is to look mechanistically at how the microbiome alters tumour biology. One way they will do this is by growing organoids, which are self-renewing 3D tissue cultures, using stem cells from patients and looking at how adding different microbes impacts their function. This system can also be used to look at interactions with the immune system as well as therapies that are currently approved for colorectal cancer treatment.
Furthermore, Beth is contributing to the establishment of a phase 0 clinical trial in which the aim is to target one aspect of the immune system, which is believed to be detrimental in a subset of colorectal cancer patients. The researchers are currently planning the trial which is aimed at assessing safety and determining biologically whether they can see any effect of the treatment in tumour tissue by looking at biopsies.

Across several projects Beth is collaborating with a vast number of researchers: within the CRUK Grand Challenge (a list of all researchers involved can be found on the OPTIMISTICC website), Beth is also closely collaborating with Prof. Tim Maughan (Department of Oncology) and the S:CORT team, several colleagues in OCTO are helping to facilitate the clinical trials.

Beth’s work is funded by CRUK (Grand Challenge) and the MRC (Experimental Medicine Challenge Grant).

Using Cancer Big Data to improve Patient Treatment and Stratification

Andrew Blake is the Strategic Data Platform Development Lead at the Cancer Research UK Oxford Centre and for the S:CORT consortium. He has a degree in human genetics and a master’s in bioinformatics. Andrew has created a variety of bioinformatics databases, web portals and developed analysis pipelines as well as spearheading the system administration of the high availability, high performance computing infrastructure supporting EU wide and international programmes. He played a key role in an international bioinformatics consortium working closely with the European Bioinformatics Institute (EBI) and the Welcome Trust Sanger Institute. Andrew is now working with complex multi-parametric cancer datasets (including DNA sequencing, RNA expression, DNA methylation, IHC and clinical patient data) across a range of digestive cancers including Oesophageal and Colorectal, applying the best practises in bioinformatics pipeline development, data standardisation, computing infrastructure, data visualisation and collaborative tools that underpin discovery and validation of a series of novel cancer patient stratification signatures.

Bowel Cancer is a complex disease, many researchers apply different laboratory based techniques to identify novel ways of diagnosing and treating patients. Andrew identifies the latest information technologies to support these researchers providing quality control, analysis and interpretation of their big cancer datasets and facilitates sharing the data across researchers with complementary interests.

Andrew and the S:CORT team are looking at patient response to chemotherapy, radiotherapy and surgical intervention as well as novel therapeutics in order to stratify patients to receive the most appropriate treatment based on their biomarker data. By determining a patient’s potential response or non-response to a treatment this research can offer clinicians the best knowledge to plan each patient’s treatment so that they receive the right therapeutic options as their first line therapy.

Andrew’s collaborators within S:CORT are Peter Campbell (Welcome Trust Sanger Institute), Dr Andrew Beggs, Professor Ian Tomlinson and Professor Dion Morton (University of Birmingham), Professor Manuel Salto-Tellez and Dr Philip Dunne (Queens University Belfast), Professor Philip Quirke  (University of Leeds), Louise Brown and Professor Rick Kaplan  (MRC Clinical Trials Unit), and commercial partners Almac Diagnostics and Indica Labs.

MRC and CRUK are funding Andrew’s work on S:CORT, he receives further funding through the CRUK Oxford Centre.

 

Improving Patient Stratification and Treatment

Dr Annabelle Lewis is a Group Leader based at the Wellcome Trust Centre for Human Genetics. Annabelle studied Natural Sciences at the University of Cambridge as an undergraduate, and went on to completed a PhD and postdoc at Dr Wolf Reik’s laboratory in the Babraham Institute, investigating the epigenetic regulation of imprinted genes. She then moved to work on the genetics of colorectal cancer in Prof Ian Tomlinson’s laboratory in the CRUK London Research Institute and subsequently the Wellcome Centre for Human Genetics (within the Nuffield Department of Medicine). Annabelle is investigating the functional roles of cancer risk variants of colorectal cancer in gene regulation, specifically their role in regulating methylation in the promoter of the DNA repair gene MLH1.

There are currently over 100 common genetic variants associated with an increased risk of colorectal cancer. However most of this information has yet to be usefully translated into the clinic. Most of the DNA variants that increase colorectal cancer risk do not mutate protein sequences. It is presumed that they modify the levels of gene activity and the amount of protein produced. The aim of Annabelle’s research is to find out the target gene of each variant, whether the risk variant turns this gene up or down, how it does this and then why different amounts of the gene product increase the chance of cancer. This knowledge will identify gene products that can be targeted with existing therapy or novel drug targets. It will also help to stratify cancer patients into groups which will respond well or poorly to therapeutic regimes. They also aim to identify groups of the population who would benefit from increased or early screening. Ultimately, this will help patients receive the most effective and appropriate treatment for their individual cancer.

Within Oxford, Annabelle is collaborating with Dr David Church, Prof Catharine Green and Prof Simon Leedham (Wellcome Trust Centre for Human Genetics), Prof Timothy Maughan and Prof Eric O’Neill (Department of Oncology), Prof Gareth Bond, Prof Skirmantas Kriaucionis and Dr Benjamin Schuster-Böckler (Ludwig Institute for Cancer Research).
Further collaborators are Prof Ian Tomlinson, Dr Roland Arnold and Dr Claire Palles (University of Birmingham), and Prof Daniela Furlan (Università dell’Insubria Varese, Italy).

Annabelle’s research is funded through the New Investigator Research Grant from the Medical Research Council and a MRC Harwell IMPC grant.

 

 

 

Predicting Bowel Cancer

Nadia Nasreddin is an experimental biologist and first year DPhil student in Clinical Medicine based at the Wellcome Centre for Human Genetics (Nuffield Department of Medicine).  She undertook her first degree in Biomedical Sciences and then did a master’s in Human Molecular Genetics. Nadia then worked as a research assistant at the Wellcome Centre for Human Genetics in Prof Simon Leedham’s lab. Her main area of research is colitis and colitis-associated colorectal cancer (CA-CRC), principally looking into the link between inflammation and tumourigenesis.

Human IBD dysplastic sample – example of LGD highly infiltrated with immune cells – To be able to molecularly phenotype the lesions laser capture microdissection (LCM) is used to isolate the crypts. Image with courtesy from Nadia Nasreddin.

Individuals suffering from inflammatory bowel disease (IBD) are at a significantly increased risk of developing colon cancer. Consequently, IBD patients are subjected to intensive surveillance programmes, aiming to detect cancer precursor lesions in their early developmental stages. However, the effectiveness of these programmes is compromised by several factors, in addition to being costly and invasive. Even following detection of these early cancer precursor lesions, the need for colectomy is highly contentious and represents a major clinicla issue.
Nadia is currently working on a project undertaking an integrated omics analysis of colitis-associated lesions with the aim of validating and clinically testing a cost-effective molecular biomarker, applicable to archival tissue that can stratify patients by cancer risk and help in the distinction between colitis-associated and sporadic lesions. The team is also looking into the link between the molecular profiles and digital pathology in colitis-associated lesions. As colitis-associated colorectal cancer is both clinically and molecularly different from sporadic colorectal cancer, the aim is to also elucidate its molecular pathogenesis. The ultimate goal of the study is elucidate the pathogenic pathway of  colitis-associated colorectal cancer and generate a molecular biomarker that can aid in the determination of patients’ risk, inform prophylactic decisions and provide guidance to endoscopic surveillance regiments.

Nadia’s DPhil supervisors are Prof Simon Leedham and Dr James East from the Nuffield Department of Medicine.
Collaborators include Prof Trevor Graham and his lab (Barts Cancer Institute), Dr Philip Dunne (Queen’s University Belfast) and Dr Maurice Loughrey (Belfast Heath and Social Trust).

Nadia’s DPhil is supported by the BRC (NIHR Molecular Diagnosis BRC Theme), her research project is funded by CRUK’s early detection scheme.

2019 Symposium Registration – Now open!

 

Cancer Research UK | Oxford Centre 8th Annual Symposium

Friday 28th June 2019

 

Registration & Abstract Submission NOW OPEN!

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Registration is free and exclusive to Centre members only

(Not a member yet? Sign up here)

 

The Centre’s 8th Annual Symposium will be taking place at the Said Business School, Park End Street, Oxford on Friday 28th June 2019!

Come and join us for a celebration of the passion and commitment to cancer research that is shared across our community, and the wealth of excellence which is home here in Oxford. The day will showcase the breadth of activity across the Centre and will feature cross-departmental and interdisciplinary partnerships, supporting translational cancer research.

Further information can be found on the EventBrite page.

 

 Programme:

(Details of the full programme are currently being confirmed – please keep an eye on updates here!)

 

The day will cover the below topics:

– Cancer Big Data

– Artificial Intelligence

– Molecular Omic

– Early Detection (keynote TBC)

– New to Oxford (Professor Amato Giaccia

– CRUK Research Careers (lunch time session)

– A Guest Speaker

– Poster Competitions

– The next generation of world-leading cancer researchers

Download the Symposioum’s flyer here.

 

If you are interested in the CRUK Research Careers lunch time session, please register your interest upon signing up for the conference via the EventBrite page. Please note: spaces will be limited, so please register early if you are interested, to avoid disappointment.

April is Bowel Cancer Awareness Month

In recognition of April being Bowel Cancer Awareness month, the Cancer Research UK Oxford Centre will be posting a series of blog posts on its website highlighting the contribution of Oxford researchers to global efforts aiming to tackle colorectal cancer.

Colorectal cancer is one of the most common cancers, affecting over 40,000 people per year in the UK. Sadly, it remains one of the most common causes of cancer death, despite the fact that the condition could be preventable. Almost all colorectal cancer develops from benign precursors called polyps or adenomas, and these lesions are detectable and safely removeable by an endoscopic procedure. It is this potential for prevention that led to the roll out of the national bowel cancer screening service in 2006.

Genomic investigation and biological models, such as organoids, have rapidly accelerated our understanding of colorectal cancer initiation and development in the last 15 years, and this understanding opens the way for new treatments and detection methods.

Colorectal cancer is an area of intense research activity in Oxford, and is a cornerstone of our early detection programme. Oxford researchers undertake international quality work on the basic, translational and clinical science of genetic predisposition, stem cells microenvironmental risk, the impact of the immune system, molecular and morphological stratification, new drugs and treatments and endoscopic detection.

This series of articles will summarise some of the local and national projects our researchers are leading on and contributing to, including:

 

 

 

 

 

 

Prof. Simon Leedham – Wellcome Trust Senior Research Fellow in Clinical Science and an Honorary Consultant Gastroenterologist, Head of Leedham Group

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.