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
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.
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.
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.
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.