NIHRDataInsights/HRCSData huggingface dataset:
Title: A novel epigenetic discovery pipeline for patient-tailored drug matching in glioblastoma
Funder: Cancer Research UK

Abstract: Background Malignant gliomas are the most common intrinsic brain tumours in adults and are associated with a very poor prognosis. Survival trends for these patients have not improved in the last 20 years and none of the publicly disclosed therapeutic approaches currently in development are showing promise in the clinical arena. The alteration of the glioblastoma (GBM) genome by epigenetic mechanisms that share functions with normal developmental processes, such as self-renewal and fate specification of neural stem and progenitor cells (NSC), is a key piece of evidence that links brain cancer pathogenesis with dysregulated stem cell functions. We have developed a novel strategy to compare the epigenetic make up of GBM cells (GIC) with patient-matched iPSC-derived normal NSC (iNSC). This comparison has not been feasible to date because patient-matched endogenous NSC are not surgically accessible. We have shown that iNSC are phenotypically and functionally similar to endogenous NSC and that GIC retain a similar methylation and expression profile as the bulk tumour itself. We have compared syngeneic pairs of GIC/iNSC and have shown that target genes and pathways dysregulated on a patient-specific basis can be identified using this novel pipeline. Aims We are now uniquely placed to test the hypothesis that syngeneic GIC/iNSC pairs are a suitable novel pre-clinical pipeline to accurately predict the effectiveness of matched drugs and to identify druggable targets for personalised therapy. Methods We will use phenotypic drug screening methods in GIC/iNSC syngeneic pairs combined with computational modelling of drug response prediction on a patient-specific basis to explore the validity of the established pipeline for drug repurposing and discovery. The contribution of clonal dynamics to the development of resistance will also be explored and results integrated in the drug prediction model. The most promising compounds will be validated in in vivo models, including molecular and phenotypical deconvolution to provide pre-clinical validation of the most promising compounds in vivo. How the results of this research will be used Taken together, these experiments will provide a co-ordinated approach for the identification of essential epigenetic drivers of gliomagenesis on a patient-specific basis and will provide a proof of principle that the pipeline can lead to the identification of druggable targets for personalised therapy.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Understanding the molecular basis and consequences of chemoradiosensitivity in rectal cancer in order to improve therapy (MOL-RSRC)
Funder: Cancer Research UK

Abstract: Understanding the molecular basis and consequences of chemo-radiosensitivity in rectal cancer in order to improve therapy (MOL-RSRC): Background: Rectal cancer is common, with 10,000 cases per year. Radiotherapy, combined with chemotherapy (nCRT) is the most effective non-surgical treatment to reduce post-operative recurrence rates and increase resectability. Approximately 15% of rectal cancer undergoes a complete response to nCRT but the molecular determinants of this are currently unknown. I have carried out preliminary work suggesting that a combination of DNA repair defects (mutations in FBXW7 causing defective non-homologous end joining), immunovisibility (differences in mutational burden) and epigenetic changes (hypomethylation in the PI3K pathway) are responsible for the response to nCRT. Aims: To understand the molecular determinants of chemoradiosensitivity in rectal cancer by establishing clinically relevant pre-clinical models of nCRT responsiveness. Methods: I wish to carry out further work to understand the molecular drivers of this phenomenon by establishing a collection of tumour organoids from patients undergoing nCRT, sampled at multiple points throughout the treatment process. Patients will be sampled before after treatment to understand the changes that occur during nCRT. These organoids will be genomically characterised using whole genome sequencing, RNA sequencing and epigenetic analysis at each time point. The organoid systems will then be exposed to a novel drug screen targeting pathways known to be dysregulated in rectal cancer, and the effects of drug exposure in driving resistance to therapy will be established. An integrative bioinformatical model of nCRT responsiveness using genomic and drug response data will be established to identify potential new therapies and establish their efficacy in a pre-clinical model. How the results of this study will be used: The goals of this study are to provide a series of well characterised genomic models that can elucidate the determinants of nCRT sensitivity and provide a model for further work in rectal cancer. These models will also serve as pre-clinical testbeds for the establishment of new and novel therapies.


Research activity codes: 6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Population-based, randomised controlled trial of low threshold faecal immunochemical test (FIT) versus usual care FIT in reducing colorectal cancer incidence within the Bowel Cancer Screening Programme. Short title: FIT for Screening
Funder: Cancer Research UK

Abstract: Background: Colorectal cancer (CRC) is the fourth most common cancer and second most common cause of cancer death in the UK. Screening facilitates prevention and early diagnosis, improving outcomes and reducing treatment costs. The English Bowel Cancer Screening Programme (BCSP) currently offers biennial screening with the guaiac faecal occult blood test (gFOBT) to individuals aged 60-74 years; however, the faecal immunochemical test (FIT), which only requires a single sample, has better acceptability, allows for quantitative analysis with an ability to alter the positivity threshold, and has improved sensitivity for CRC, will replace the gFOBT in 2019. FIT will be rolled-out in the BCSP with a relatively high positivity threshold in order to minimise the impact on endoscopy resources. Limited evidence exists on the impact of FIT at different thresholds on CRC incidence or mortality. Optimising the threshold is crucial to maximising the clinical and cost-effectiveness of FIT screening. Aims: We plan a nationwide randomised controlled trial (RCT) embedded in the BCSP with a primary aim to determine the effect of low- versus high-threshold (usual-care) biennial FIT screening on CRC incidence after 10-years of follow-up (five biennial screening rounds). Secondary aims include examining the effects of low- versus high-threshold FIT on: - CRC mortality - FIT positivity - Colonoscopy at successive rounds by age, sex and screening history - Detection rates of CRC and advanced adenomas by round and age, sex, and screening history - Stage of CRC at diagnosis - The predictive power of the first three rounds on results at the fourth and fifth - Cost-effectiveness analyses Methods: We will include men and women aged 60-66 years who are eligible for FIT screening in England through the BCSP. Individuals will be randomly allocated to the intervention arm (n=38,113), low-threshold (20 µg/g) FIT, or the control arm (n=152,453), high-threshold (usual-care) FIT. Analysis of FIT uptake, positivity, and diagnostic yields will be conducted at each screening round. The effect of FIT threshold on CRC incidence and cost-effectiveness will be examined after 10-years of follow-up. How the results of this research will be used: This trial will provide the first RCT evidence of the effect of different FIT thresholds on CRC incidence and mortality. Furthermore, it will provide invaluable information to inform decisions about FIT screening, by determining the implications of lowering the FIT threshold not only on CRC incidence and mortality, but also on resource usage and costs to the NHS.


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Targeting metabolic reprogramming to develop more effective and less toxic treatments for central nervous system involvement in paediatric acute lymphoblastic leukaemia.
Funder: Cancer Research UK

Abstract: Background: Cancer is the leading cause of death in children, and survivors often have lasting morbidity from the impact of chemotherapy on developing organs. The brain is particularly vulnerable; 20-40% of survivors of childhood acute lymphoblastic leukaemia (ALL) have neurocognitive deficits secondary to use of universal aggressive central nervous system (CNS) directed therapy. Despite these devastating side-effects, there have been no new drugs licensed for CNS-ALL for the last 60 years. Less toxic and more effective therapies are urgently needed. There are two main barriers to progress: 1. A lack of biological understanding of the survival mechanisms used by CNS-ALL 2. Absence of a physiologically relevant drug-discovery pipeline for CNS-active drugs. This programme builds on pioneering work from my laboratory which developed tractable models of CNS-ALL to identify relationships between bone marrow and CNS-ALL. We have shown that ALL undergoes profound metabolic reprogramming in the CNS-niche and identified lipid and cholesterol biosynthesis as clinically relevant targets. Aims: Three complementary work packages (WP) aim to deepen understanding of the key biological mechanisms underlying ALL survival in the CNS microenvironment and translate these into improved treatments. In WP1 we investigate the functional consequences of cell-autonomous metabolic reprogramming in CNS-ALL, thereby identifying critical vulnerabilities. This is complemented by studies in WP2 that uncover metabolic interdependency between ALL and the CNS niche. The final WP3 is translational and focuses on the design of rational combination therapies targeting metabolic vulnerabilities, and any compensatory rewiring, in CNS-ALL. Methods: This programme brings together a world-class team to support the development of an internationally leading research programme in CNS-ALL. It utilises cutting-edge metabolomics and lipidomics technology, integration of ‘omic’ data and development of novel physiological in vitro models of CNS-ALL, accompanied by a preclinical pipeline using high-throughput screening and toxicity evaluation. This research will transform our understanding of how to eradicate CNS-ALL whilst protecting a child’s developing brain. How the results of this research will be used: This innovative programme will drive clinical advances in treatment of CNS-ALL by building a strong scientific understanding of disease biology and using this to develop novel treatments. The goal is to deliver rationally designed low-toxicity CNS-directed therapy. This therapy will reduce toxicity for all patients and improve survival for those with CNS-relapse.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Improving immunotherapy efficacy and defining the tumour antigen landscape that is recognized by CD8 T-cells in microsatellite stable colorectal cancer
Funder: Cancer Research UK

Abstract: Background New therapies are needed to improve the survival of patients with microsatellite stable (MSS) colorectal cancer (CRC). We have shown that MSS CRCs that have been treated with anti-EGFR antibodies become infiltrated by CD8 T-cells and upregulate the PDL1 and LAG3 immune-checkpoints. This suggests that inhibitors of these immune-checkpoints may be effective following anti-EGFR antibody treatment. Using mass spectrometry of patient-derived CRC organoids, we furthermore found that neoantigens, which are considered important targets of CD8 T-cells during immune-checkpoint inhibitor treatment, are much sparser than previously thought. Indeed, which and how many antigens can be recognized by T-cells in MSS CRCs remains unknown. This hinders the design of better immunotherapies and biomarkers. Aims We will investigate the efficacy of anti-PD1 and anti-LAG3 combination immunotherapy in a clinical trial in MSS CRC patients who were previously treated with anti-EGFR antibodies, and identify predictive biomarkers and immunosuppressive mechanisms that hinder responses. We will furthermore assess which antigens can be recognized by T-cells on the surface of CRC cells and whether this can inform the development of T-cell receptor (TCR) engineered therapies. Methods The molecular and cellular characteristics of serial biopsies from CRCs treated with PD1/LAG3 combination will be interrogated by multiplex immunostaining, exome-, RNA- and TCR-sequencing to identify mechanisms of response and resistance. Patient derived organoids (PDOs) will be expanded from CRCs followed by computational and mass spectrometry-based identification of antigens presented on MHC class I. Which neoantigens and non-mutated tumour associated antigens can be recognized by T-cells will be investigated in autologous PDO and T-cell co-cultures through multiplex multimers and T-cell receptor (TCR) sequencing. Finally, TCRs recognizing recurrently presented antigens will be cloned and expressed in T-cells and cytotoxicity against CRC PDOs and cell lines will be tested. How the results of this research will be used Our results will help change the way immunotherapies are developed in MSS CRC, from empirical testing of new immunotherapy drugs to a data- and hypothesis-driven approach. Candidate predictive biomarkers for PD1/LAG3 immunotherapy will be used for patient stratification in follow-on trials. The identification of immunosuppressive mechanisms that hinder PD1/LAG3 treatment responses will inform the rational combination immunotherapy trials that co-target these mechanisms. The detailed analysis of the antigen landscape that is recognized by T-cells should lead to the development of novel TCR-engineered therapies and more effective cancer vaccines.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Catch up HPV screening project
Funder: Yorkshire Cancer Research

Abstract: In 2019, HPV testing replaced cytology (a smear) as the first (primary) cervical screening test. This project will offer a catch-up HPV test to women now aged 65-79 who exited the screening programme before ever having a primary HPV test. This will identify women at risk of developing cervical cancer. To save women from the sometimes painful intimate examination necessary for a traditional smear, we will ask them to send a urine sample which is just as good for picking up HPV. We hope this will encourage women who were not screened regularly to take part. Women testing HPV positive will be referred to a research colposcopy clinic for further tests and treatment. The research will be done working with GP practices in Manchester and Hull, first inviting 3,000 women to test how it works, and then inviting a further 15,000 women, aiming to screen around 10,000 women. We will compare uptake rates, levels of HPV and diagnoses of pre-cancer and cancer between those who have been previously regularly screened and those who have not. This will allow us to estimate whether all women aged 65-79, including those who were screened regularly, would benefit from a catch-up programme.

Lay abstract: In 2019, HPV testing replaced cytology (a smear) as the first (primary) cervical screening test. This project will offer a catch-up HPV test to women now aged 65-79 who exited the screening programme before ever having a primary HPV test. This will identify women at risk of developing cervical cancer. To save women from the sometimes painful intimate examination necessary for a traditional smear, we will ask them to send a urine sample which is just as good for picking up HPV. We hope this will encourage women who were not screened regularly to take part. Women testing HPV positive will be referred to a research colposcopy clinic for further tests and treatment. The research will be done working with GP practices in Manchester and Hull, first inviting 3,000 women to test how it works, and then inviting a further 15,000 women, aiming to screen around 10,000 women. We will compare uptake rates, levels of HPV and diagnoses of pre-cancer and cancer between those who have been previously regularly screened and those who have not. This will allow us to estimate whether all women aged 65-79, including those who were screened regularly, would benefit from a catch-up programme.

Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: In-depth characterisation of the evolutionary origins and migration patterns of metastasis at single-cell whole-genome resolution
Funder: Cancer Research UK

Abstract: Background: Metastasis results from the complex process of cancer-cell dissemination and is the most common cause of cancer-related mortality. An in-depth understanding of this process would allow us to develop insights into the cellular mechanisms permitting cancer-cell dissemination and might lead to new therapeutic strategies to improve patient outcomes. However, this endeavour has been constrained by the limitations of standard bulk sequencing, especially the lack of power to unambiguously identify distinct, small subpopulations of cancer cells that play an important role in metastasis. As a result, little is currently known about the evolutionary origins of metastatic cells and their migration patterns. Aims: I aim to characterise the metastatic process using cutting-edge single-cell whole-genome sequencing technologies, which provide the resolution required to investigate such a complex process. Existing computational methods cannot be used to accurately analyse the data generated by these new technologies, as they are characterised by substantially different features compared to standard bulk sequencing. Therefore, we aim to develop the first single-cell-specific framework of computational methods for the accurate analysis of single-cell whole-genome sequencing data. These novel methods will be applied to comprehensively characterise metastatic evolution and migration patterns from an unparalleled dataset that we aim to generate from thousands of single metastatic cancer cells. Methods: I propose to use the revolutionary Direct-Library Preparation+ technology to sequence the whole-genome of 192,000 single metastatic cells from 96 tumour samples of 20 non-small-cell lung cancer patients. We will develop new single-cell-specific methods, which will address the challenges of single-cell whole-genome sequencing data by jointly and simultaneously analysing thousands of evolutionarily-related cancer cells obtained from each patient. Importantly, these methods will enable a new generation of cancer evolutionary analyses that are critical for understanding metastasis, such as characterising small subpopulations of metastatic cells. How the results of this research will be used: These methods will be used to unravel the biological complexities of metastasis and related therapeutic opportunities from the generated data. I envision that the proposed in-depth analysis will reveal genetic and evolutionary hallmarks of metastases that will allow us to stratify cancer phenotypes and develop therapeutic strategies to improve patient outcomes. Importantly, these methods will not only be applicable to the generated data but also to other datasets of different cancer types and to other rapidly-expanding single-cell technologies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Exploiting membrane dynamics to target the assembly of the metastatic matrix niche in ovarian cancer
Funder: Cancer Research UK

Abstract: BACKGROUND Ovarian cancer has a 5-year survival of only 40% and the outlook is worse for the most common form, high-grade serous ovarian cancer (HGSOC). The major lethal step in HGSOC progression is intracoelomic metastasis. This proposal aims to determine the mechanisms that establish the metastatic niche for HGSOC. Cancer associated fibroblasts (CAFs) assemble an aberrant matrix to generate the niche that supports HGSOC proliferation and invasion at metastatic sites, but the mechanisms of matrix assembly are unknown. We hypothesise that plasma membrane tension and vesicle trafficking pathways cooperate to coordinate the delivery and remodelling of matrix molecules at the plasma membrane to generate the metastatic matrix niche. As metastasis is the primary cause of recurrent disease and patient death, agents that suppress the niche could prolong patient survival and improve quality of life. AIMS We will determine how membrane dynamics coordinate the assembly of the aberrant matrix niche in HGSOC. Two central hypotheses will be tested: 1. Endocytic recycling pathways carry cargos to the plasma membrane to coordinate the assembly of aberrant matrix. 2. Plasma membrane tension generates local signals that control the cytoskeleton and matrix remodelling. METHODS Established collaborations afford access to metastatic niche cells and tissue from HGSOC patients. From these we generate primary CAF and metastatic cancer cell cultures to define new mechanisms of aberrant matrix assembly and metastatic niche formation. Combining cutting edge imaging and proteomics approaches we will determine the endocytic recycling pathways and key cargos that control the generation of the matrix niche by CAFs. We will reveal the role of membrane tension as a mechanical signal controlling CAF contractility and matrix remodelling, and how the interplay between membrane tension and vesicle trafficking controls CAF behaviour. Using organotypic 3D matrix and mouse models we will define how membrane dynamics supports HGSOC metastasis. By testing our findings in cells isolated from patients post-chemotherapy, we will explore the function of metastatic niche assembly in resistance to therapy. HOW THE RESULTS OF THIS RESEARCH WILL BE USED This programme of research will establish new paradigms in HGSOC progression, revealing the mechanisms that underlie aberrant matrix changes and create the metastatic niche for HGSOC. Interrogating metastatic niche formation using defined patient cells/tissues will establish the clinical potential for targeting matrix assembly to prevent HGSOC metastasis and recurrence.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS