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.