NIHRDataInsights/HRCSData huggingface dataset:
Title: Tissue-resident macrophages and malignant progression of ovarian cancer
Funder: Medical Research Council

Abstract: Hypothesis: This project will test the hypothesis that specific axes of interaction between Tissue-Resident Macrophages (TRM) and disseminated cancer cells promotes their malignant progression and the development of invasive disease. Objecitve: Our objective is to unravel the molecular basis of these interactions that may in turn reflect viable clinical targets. Approach: Our approach includes in-depth descriptive studies coupled with in vivo validation in experimental models, with the aim to achieve a finer definition of TRM and identify new therapeutic targets. We will build on our previous work and map the molecular dialogue between TRM and cancer cells using parallel single cell analysis in new clinically relevant models of HGSC. We will also generate new and unique tools to probe the function of TRM in these models and validate their roles in tumour progression. Outcome: These studies will provide new insights into the tumour-promoting functions of TRM and reveal molecular targets to support the development of TRM targeted therapies for human cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Mechanisms of uncoupling cellular growth from mTOR pathway activity
Funder: Medical Research Council

Abstract: The mechanistic target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that acts as a rheostat of energy in all eukaryotes. mTOR senses a variety of inputs such as nutrients, growth factors, oxygen, and stress and, accordingly, regulates core decisions and cellular processes including protein synthesis, growth, metabolism, ageing, and autophagy. Activation of mTOR promotes tumour growth and metastasis. While some of the mTOR inhibitors have been developed and approved to treat human cancer, more mTOR inhibitors are being evaluated in clinical trials. Due to the fundamental roles of mTOR in growth, cell cycle progression and anabolism within all eukaryotes, resistance to mTOR inhibition itself is a major problem, partly attributed to the large heterogeneity of cancer cells. Over-activating mTOR kinase mutations as well as Myc- and PI3K-dependent mTOR resistance have been reported. However, a comprehensive genetic roadmap and involved mechanisms that result in bypassing the requirement for mTOR activity in cellular growth have remained poorly defined. Our preliminary data strongly show that cells are able to uncouple cellular growth to nutrient availability and mTOR activity through diverse pathways. Through the proposed work, we will provide a global view of conserved genetic factors that modulate resistance to mTOR inhibition. We will reveal connections and define underlying mechanisms involved in resistance. We will utilise the relevant and established for cell cycle, growth and ageing studies, fission yeast (Schizosaccharomyces pombe), making use of its vast genetic and genomic resources. In addition, our findings will be extended and validated to established, in our lab, human tissue systems. Our results will lead in a better understanding of nutrient- and growth factor-dependent cellular growth and will highlight the key candidates for targeting resistant cancer cells.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Deciphering the role of RNA localisation in cancer progression
Funder: Medical Research Council

Abstract: Recent studies have shown that the majority of eukaryotic RNAs are localised to specific subcellular compartments. However, how spatial organisation of RNAs impacts on post-transcriptional regulation, and how this is dysregulated in diseases such as cancer, remains unclear. Our previous studies have demonstrated that RNA localisation to actin-rich protrusions plays an important role in regulation of growth and invasion in highly aggressive cancers (Mardakheh et al., 2015, Dev Cell; Dermit et al., 2020, Dev Cell). This raises the possibility that RNA localisation to other subcellular compartments may also play an important role in cancer progression. To study the role of RNA localisation in a systematic manner, we have developed a novel multi-omics method named Crosslinking & Fractionation (CLIF), which enables genome-wide profiling of RNA and protein localisations to different subcellular compartments. Using this method, we have revealed several changes in RNA localisation patterns that occur in a model of breast cancer progression. In this proposal, we aim to reveal which of these patterns of RNA localisation change are conserved during the progression of human breast cancers, assess their functional impact on post-transcriptional regulation of the affected transcripts, before dissecting the molecular mechanisms that mediate the localisation changes during malignant progression. We will then assess the functional impact of the identified RNA localisation-mediated dysregulations on breast cancer progression, in vivo. This work will systematically uncover novel post-transcriptional mechanisms that regulate cancer progression through RNA localisation. Since a significant degree of gene expression dysregulation that occurs in cancer is post-transcriptional, our findings will have profound implications with regards to how such dysregulations can be detected via monitoring RNA localisation, or therapeutically targeted via interfering with the localisation mechanisms.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: A translational programme to elucidate the pathophysiology of oesophago-gastric cancer and develop clinical innovations
Funder: Medical Research Council

Abstract: Oesophageal and gastric cancer, including cancers arising at the gastro-oesophageal junction, are the sixth most common cause of cancer mortality worldwide (Globocan 2018). The outcomes are poor because of late diagnosis. Since these cancers develop gradually from pre-cancerous metaplastic states there is the opportunity to pre-empt the development of advanced disease. The oesophagus and stomach are ideally suited for studies of cancer evolution since they are highly accessible. In Cambridge we have assembled a highly valuable data and sample resource comprising >3,000 cases with pre-cancer followed longitudinally. The group spans experimental biologists, computational scientists and clinicians with expertise in novel diagnostics, including state of the art endoscopic imaging, and the pan-oesophageal Cytosponge sampling device which we developed. We can thus map cell and molecular alterations over time and space, down to single cell resolution, in high risk patients. In vitro models, including 3D organoids derived from the same patients, allow us to manipulate the oncogenic drivers and alter the micro-environmental cues, to determine the triggers for malignant transformation and progression. We will use probabilistic models to distinguish predictors of indolent compared with aggressive disease trajectories. Resarch aims: i) Elucidate the mechanisms underlying causative mutational processes in oesophago-gastric cancer; ii) Distinguish the origin of cancers with distinct disease trajectories and iii) Develop clinical risk prediction models, including use of novel endoscopic tools for detection of dysplasia and molecular analysis of Cytosponge samples. Through our collaborations and proximity to Clinical Research Facilities we are ideally placed progress our findings to clinical trials to improve outcomes for patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Development of peptide-drug conjugates for the treatment of Chronic Myelomonocytic Leukaemia (CMML)
Funder: Medical Research Council

Abstract: Chronic Myelomonocytic Leukaemia (CMML) is an orphan disease defined by myeloid dysplasia, myeloproliferation and malignant expansion of classical monocytes. There is no generally effective treatment, so for the majority of patients prognosis is dismal, with median survival of 15-20 months. Chemotherapeutic approaches in CMML (and other leukaemias) frequently fail due to a lack of specificity, or insufficient activity against disease initiating/sustaining progenitor cells in the bone marrow niche. We are seeking to address this unmet need by developing a new class of CCL2-drug conjugates that mobilise CMML progenitor cells and selectively kill CMML cells throughout the disease clone. C-C chemokine receptor type 2 (CCR2) is a chemokine receptor that is expressed almost exclusively on cells of monocytoid lineage, including the expanded classical monocyte population characteristic of CMML and the progenitors that propagate the disease, as well as blasts of monocytoid lineage from other myeloid malignancies. CCL2, the ligand for CCR2, mediates mobilisation of monocytoid cells from the bone marrow and chemotaxis of mature monocytes. We have demonstrated that; 1) active uptake of CCL2 by CCR2+ cells can be exploited to selectively deliver a small molecule payload to the cytoplasm, 2) CCR2 is highly expressed on the most relevant populations/stages of CMML, 3) conjugation of a novel cytotoxic payload to CCL2 results in a targeted agent that exhibits cell-cycle independent cytotoxicity after 48-96 hours (CC50 1-10 nM), 4) CCL2 conjugates rapidly and comprehensively target all CCR2+ cell populations in vivo, resulting in a 50% reduction in circulating CCR2+ cells 48 hours after a single administration. The overall objective is to de-risk critical aspects of the programme by; 1) further building the platform of evidence for our approach and identifying a clinical candidate and 2) conducting a package of pre-clinical studies to de-risk further translation of this agent.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Elucidating how Dysbiosis, Senescence and Inflammatory Storms Impact Prostate Carcinogenesis and Treatment Resistance to Transform Care.
Funder: Medical Research Council

Abstract: BACKGROUND: Prostate cancer (PCa) is the commonest male cancer in the UK, with 1 in 8 men developing PCa (50,000/year) and a man dying from PCa every 45-minutes in the UK. PCa is also increasing in incidence globally probably due to diet/lifestyle changes, including in Africa and Asia. We have transformed understanding of PCa biology, genetic risk, genomics, and care, developing molecular stratification and blood-based biomarkers. Despite this, PCa still causes major morbidity and mortality. Novel prevention and therapeutic strategies are urgently needed. PRELIMINARY DATA: We have data supporting a model of prostate carcinogenesis that implicates self-perpetuating inflammatory storms resulting from cell senescence and induced by oncogenic insults generating oxidative stress, DNA damage at exposed chromatin including DNA repair genes and androgen receptor response elements. This process is accelerated by germline DNA repair defects and SNPs increasing AR signalling. HYPOTHESES: We hypothesise that diet, GI dysmotility and dysbiosis drive prostate carcinogenesis and can impact outcomes to established treatments, at least in part by impacting paracrine intercellular relationships. AIMS: 1) We will elucidate in PCa models how diet content (lipid; fibre), gut dysmotility and dysbiosis impact prostate epithelial cell oncogenic insults to drive senescence, SASP related inflammation, and fuel inflammatory storms that cause DNA damage, activate DNA repair and oncogenic events. 2) We will also determine how these impact outcomes from established treatments including radiotherapy, endocrine therapy, taxanes and PARP inhibition. 3) Finally, we will dissect putatively paracrine inter-cellular relationships between prostatic and inflammatory cells that fuel PCa development, growth and survival utilising immunocytochemistry, single nucleus RNAseq and co-culture studies. IMPLICATIONS: We will develop novel, transformative, PCa prevention and treatment strategies.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS
Title: Dissecting the role of macrophage-derived cysteine cathepsin S in lung adenocarcinoma
Funder: Medical Research Council

Abstract: There are more than 47,000 diagnosed UK cases of lung cancer (LC) each year. Non-small cell lung cancer (NSCLC) accounts for the majority of these cases, and lung adenocarcinoma (LUAD) is the most common NSCLC sub-type (~40%). Kirsten Rat Sarcoma viral oncogene homolog (KRAS) is commonly mutated in LUAD and oncogenic KRAS activation significantly impacts the tumour immune microenvironment (TME). Indeed, LUAD cancers are often hyper-inflamed with immune cells from the myeloid lineage the most frequently observed population. Macrophages are a highly plastic family of immune cells and exhibit a variety of phenotypes, including an M1 phenotype which are deemed classically activated, pro-inflammatory with anti-tumour activity, while the M2 phenotype are alternatively activated, proangiogenic and immunosuppressive with pro-tumour activity. Tumour associated macrophages (TAMs), are governed by the nature of the local microenvironment. Furthermore, they make up a significant proportion of tumour-infiltrating immune cells in human and mouse LUAD, are often skewed towards this pro-tumour "M2-like" phenotype which aids in tumour progression through enhanced angiogenesis, local invasion and distant metastases. M2-like TAMs produce elevated levels of cysteine proteases, including cathepsin S (CatS), that has previously been shown to enhance tumour growth, invasion, angiogenesis and pro-tumour inflammation. Previous studies have shown that inhibition of CatS can impede macrophage infiltration and inflammation and diminish tumour growth, limiting TME remodelling and metastases. While we have demonstrated that extracellular CatS has a potent, damaging impact in other chronic respiratory diseases, but its role in LUAD is yet to be elucidated. Therefore, this project will uncover how CatS contributes to the varying stages in KRAS mutant LUAD tumourigenesis and how targeting CatS could improve therapeutic strategies for this poor prognostic tumour subtype.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: New chemical biology approaches to study P2Y2 receptors in health and disease
Funder: Medical Research Council

Abstract: Activation of purinergic P2Y2 receptors by ATP and UTP released from damaged cells plays a significant role in inflammatory conditions, and the receptor is an important therapeutic target in many areas of clinical need. The elucidation of the receptor signalling and subsequent drug discovery has lagged behind that of other GPCRs due to the lack of commercially available P2Y2R radio-labelled ligands and stable high affinity P2Y2R ligands. We will expand on our previously reported structure activity relationship (SAR) in a series of stable P2Y2R antagonists, increasing the affinity of these compounds alongside improving physicochemical properties, such as solubility. We will synthesise P2Y2R antagonist chemical scaffolds with attachment points to carry out high speed synthetic chemistry to explore linking groups from the chemical scaffold to a fluorescent probe. We have previously reported on the synthesis of such ligands, however our present plan is to increase the affinity of the fluorescently labelled ligands to develop novel fluorescence based ligand binding assays for future lead generation programmes. We will design and synthesise novel, non-nucleotide P2Y2R agonists and P2Y2R agonist chemical scaffolds to explore linking groups from the chemical scaffold to fluorescent probes. The high affinity selective P2Y2R agonist probes will be used to gain valuable insight into cell signalling processes in both healthy and diseased cells. The chemical biology tools will study the interaction between the P2Y2R and other key mediators, such as VEGFR2, responsible in life threatening diseases such as cancer and IPF. In combination with the chemistry-driven design programmes, structural work will be explored through a combination of the emerging P2Y2R homology model and the information generated within this research project. Valuable insights could be applied to other purinergic receptors, offering the design of new ligands for therapeutic benefit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Access Cancer Care India: affordable, integrated multi-cancer early detection to improve equitable cancer outcomes
Funder: Medical Research Council

Abstract: There are several evidence-based strategies to potentially improve the access and quality of cancer early detection for the rural vulnerable populations in India. Our study will evaluate which of these strategies are implementable in a range of settings, and once implemented whether they can address the local needs, capacities and expectations, and what factors determine this. Finally, we will also assess scalability and sustainability of the interventions with proven effectiveness. There is an urgent need to tailor promotive health care to the changed health delivery system in the post- COVID-19 era. Our planned study will give an opportunity to objectively evaluate the impact of the pandemic in the context of access to cancer early detection and treatment. Fit of Study within Call This study focuses on implementation research for a well-validated, integrated early detection interventional approach for cancer (secondary prevention) in the context of a complex lower middle- income country, India. The three states for the study provide different and comparative implementation ecosystems to dissect out critical issues and barriers (logistical, political, social and economic) to support national scale up and inform other comparable countries globally. This intervention targets three site-specific cancers - oral, cervical and breast - that, combined are responsible for 28% of premature mortality in India and 12% globally, in particular for women. Scaling up these proven secondary prevention interventions would significantly address 1/3rd reduction in premature mortality as part of SDG 3.4, and our focus on the most vulnerable populations (the rural populations in some of the hard to reach areas in India) will ensure this approach meets WHO's ambition of expanding Universal Health Coverage to a billion population.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Autologous chimeric antigen receptor T cells targeting CCR9 for the treatment of T acute lymphoblastic leukaemia
Funder: Medical Research Council

Abstract: T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy of immature T cells. While approximately half of adults with T-ALL can be cured with conventional therapy, relapsed and refractory (r/r) disease carries a poor prognosis. There is no standard of care, and most patients receive intensive salvage chemotherapy with a view to allogeneic haematopoietic stem cell transplant (allo-HSCT). This treatment pathway is highly toxic and rarely successful, with long-term survival <10%. No promising new treatments are available for T-ALL. By contrast, chimeric antigen receptor (CAR)-T cell therapy is revolutionising the treatment of patients with r/r B cell ALL (B-ALL), a closely related disorder. Here, many patients have durable responses after CAR-T. Replicating this success in T-ALL has thus far proven difficult. In B-ALL, pan-B cell antigens (like CD19) can be targeted by CAR-T, since the concomitant normal B cell aplasia is clinically tolerable. An analogous approach in T-ALL, resulting in targeting of normal T cells, faces two problems. Firstly, the CAR-T cells would target each other (so-called fratricide); if this problem could be overcome, depletion of the normal T cell compartment would lead to unacceptable immunosuppression. Absent to date is a target expressed on T-ALL but not on normal T-cells. We have identified such an antigen, demonstrating that C-C chemokine receptor type 9 (CCR9) is expressed on ~85% of cases of r/r T-ALL, with expression on normal tissues limited to <5% of normal immune cells. We have developed anti-CCR9 CAR-T cells and shown potent anti-leukaemic activity in vitro and in vivo, using cell line models and patient-derived xenografts. We hypothesise that anti-CCR9 CAR-T cells is a safe and effective treatment strategy for T-ALL and propose a phase-1 first-in-human clinical trial with our CAR. The development of an effective CAR-T treatment for patients with r/r T-ALL would be a major advance in a neglected clinical area.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Detection of circulating cell free tumour DNA in renal cancer patients for the prediction and detection of early disease recurrence
Funder: Medical Research Council

Abstract: We aim to use clear cell renal cell carcinoma (ccRCC) specific differentially methylated regions to identify ccRCC circulating cell-free tumour DNA (ctDNA) in ccRCC patients' plasma and assess whether this ctDNA can be used for predicting disease recurrence and monitoring for minimal residual disease following apparently curative surgery. To do this a synthetic ccRCC specific ctDNA profile has been constructed from publicly available methylation data from ccRCC tumours, leucocytes, erythrocytes and healthy tissue. This profile will be validated using the illumina methylation EPIC array in ccRCC tissues from primary and metastatic tumours available in the Edinburgh Renal Cancer Biobank, using the illumina EPIC array. Plasma from ccRCC patients and healthy controls, available from the Edinburgh Renal Cancer Biobank, will be interrogated to identify this methylated ctDNA profile. This will be performed using innovative and locally developed Nonacus technology that allows the identification of up to 10K methylated CpGs in a sample. Correlation between ctDNA findings and primary tumour tissue will be made with selected re-profiling of the primary tumours using the illumina EPIC array. Plasma samples across the spectrum of RCC stages at presentation and then during follow-up after surgery will be assessed for the presence of methylated ctDNA and linked with high-quality, well annotated clinical data. Correlation between ctDNA findings and clinical and outcome data in the ccRCC patients and healthy control cohorts detailed will allow us to assess the utility of plasma ctDNA for the prediction of outcome following surgery and monitoring for disease recurrence.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS