NIHRDataInsights/HRCSData huggingface dataset:
Title: Understanding the Evolution of Late Breast Cancer Relapse as a Route to Improving Clinical Outcome
Funder: Wellcome Trust

Abstract: Patients with oestrogen receptor positive breast cancer frequently develop metastatic relapse, a fatal condition, many years after apparent cure. These relapses arise from persistent disseminated tumour cells (DTCs). Technical and logistic factors have made this a challenging disease entity to study in the past. Hosted by a world leading molecular sequencing institution, I will combine pioneering genomic technologies with an absolutely unique sample resource to address this complex clinical problem. The goals of my research are to: 1. Define the evolutionary patterns that underlie late oestrogen receptor positive breast cancer relapse including its relationship to bone marrow DTCs. 2. Determine if the genomes of DTCs harbour a signal that is likely to be informative about future disease trajectories. These aims will be achieved by applying diverse bio-informatic approaches to whole genome and whole transcriptome data derived from multi-region sampled primary tumours, metastatic deposits and bone marrow DTCs (single cell G&T-seq) obtained at first diagnosis and during clinical remission. The results from these studies will be of fundamental importance for strategies that aim to predict and prevent long-term relapse from breast and potentially, other common cancers. The datasets generated and informatic tools developed will be of major interest across the life-sciences.

Lay abstract: Breast cancers frequently relapse many years after apparent cure. Late relapse is difficult to predict and because it is usually incurable, prevention is an important clinical challenge. Relapses arise from persistent Disseminated Tumour Cells (DTCs), which can often be found in the bone marrow during disease-free follow-up and are thought to exist in a ‘dormant’ (sleeping) state. I aim to understand how late relapses arise, determine if the genetic features of DTCs predict for cancer recurrence and potentially identify therapeutic vulnerabilities of the DTCs themselves. Cutting edge genomic techniques will be applied to a unique collection of samples from patients’ primary breast cancers, late relapses and bone marrow. Computational analyses will reveal the evolutionary events that underlie the extraordinary behaviour of this disease. This study will provide insights into cancer dormancy and provide a rational basis for developing new, much needed approaches for predicting and managing late breast cancer relapses.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Defining WNT/beta-catenin control over immunosurveillance and immune escape in colon cancer
Funder: Cancer Research UK

Abstract: BACKGROUND The importance of conventional CD8 T-cells is well established in colorectal cancer, as their abundance in tumours predicts a good outcome in cancer patients. However, for the largest group of colorectal cancers – the microsatellite stable (MSS) group, which represents 80-85% of cases – CD8 T-cells are largely absent from tumours. Patients with MSS tumours respond poorly to anti-PD-1. Thus, a greater understanding of other cytotoxic immune cells in MSS tumours is required to develop novel immunotherapies. Across the genomic landscape of MSS tumours, mutations in WNT/beta-catenin-related genes are the strongest correlative of low T-cell infiltration. Thus, the overall goal of this proposal is to mechanistically dissect the interaction between WNT/beta-catenin signalling, immunosurveillance and immune escape in colon cancer. This proposal will specifically focus on intraepithelial lymphocytes (IELs), a group of gut-resident, unconventional T-cells consisting of both alpha/betaT-cells and gamma/deltaT-cells, rather than conventional, dendritic cell-educated CD8+ T-cells. My lab has discovered that IELs recognize and kill pre-cancerous gut epithelial cells. However, if these IELs fail to control cancer cells early in development, mutations in these cancer cells prevent expression of IEL-associated molecules and establish IEL exclusion. AIMS My overarching hypothesis is that cancer cells subvert IEL detection via activation of the WNT/beta-catenin pathway, but this immune escape is reversible. The hypothesis will be tested in three specific aims: Aim 1: Determine how the WNT pathway (and other mutations) affects IEL recognition of pre-cancerous cells Aim 2: Determine the mechanisms underlying WNT/beta-catenin-mediated IEL exclusion during early tumorigenesis Aim 3: Determine whether inhibition of WNT/beta-catenin signalling in established tumours reverses IEL exclusion. METHODS We will utilize a combination of thoroughly characterized bowel cancer mouse models, mouse-derived intestinal organoids, organoid+T-cell co-culture systems developed in my lab, advanced imaging techniques, and human colorectal cancer transcriptomic datasets to address our research questions. We will genetically manipulate mice and organoids to establish a mechanistic link between the WNT/beta-catenin pathway, immunosurveillance and immune escape. HOW THE RESULTS OF THIS RESEARCH WILL BE USED My fundamental discoveries focused on the disrupted interaction between killer IELs and cancer cells may be used to develop strategies that reverse IEL exclusion and harness IEL cytotoxicity in MSS colon cancers. These strategies may be used in combination with anti-PD1 immunotherapy to elicit effector responses from both unconventional and conventional T-cells. These data may also extend beyond colon cancer to melanoma and other skin cancers where IELs are highly relevant.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Investigating a novel DNA replication phenotype shared by glioblastoma stem cells and neural stem cells and exploiting its therapeutic potential
Funder: Cancer Research UK

Abstract: Background Glioblastoma (GBM) is a lethal cancer driven by radioresistant cancer stem cells (GSCs). Bao et al demonstrated GSC radioresistance was due to constitutive DNA damage response (DDR) but underlying causes of DDR activation and other GSC phenotypes are enigmatic. We have shown that DNA replication stress (RS) is elevated in GSCs compared to non GSCs and is associated with higher expression of long neural genes. In support of this hypothesis identical long neural genes have recently been shown to harbour DSBs in neural stem cells (NSCs). We have also demonstrated that RS generates DNA damage in GSCs leading to DDR activation and radioresistance. Our observation that GSCs accomplish DNA replication despite slower replication rates and the presence of DSBs indicates that these cells have an aberrant DNA replication phenotype. Aims This proposal will characterise RS induced DNA damage in GSCs, investigate the aberrant DNA replication phenotype of GSCs, explore commonality with DNA replication in NSCs and evaluate RS targeted therapies in validated in vivo preclinical models. Methods 7 primary GBM cell lines cultured as paired GSC enriched and depleted populations will be utilised. RS induced DNA DSB sites in long neural genes will be confirmed via chromatin immunoprecipitation with markers of DNA DSBs and subsequent genomic sequencing. DNA replication/transcription collisions as an RS mechanism will be investigated by immunofluorescent microscopy and modulation of RNase H expression. DNA fibre assay and iPOND will characterise the novel DNA replication phenotype of GSCs. Selected techniques will demonstrate commonality with NSCs in vitro, and be compared to isogenic NSC populations engineered with common GBM mutations. The therapeutic potential of targeting RS via dual inhibition of ATR and PARP alone and in combination with radiotherapy will be evaluated in murine orthotopic GSC models. How the results of this research will be used This proposal will elucidate the mechanism(s) responsible for elevated RS in GSCs and their consequent radioresistance. We will explore the aberrant DNA replication phenotype of GSCs and investigate parallels with their putative NSC of origin. This will provide evidence that RS is a major driver of gliomagenesis and support the controversial hypothesis that NSC are the cell of origin in GBM. Finally the effects of targeting RS response pathways in GSCs will be investigated and high quality preclinical data generated to underpin and inform subsequent clinical trials.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Developing a stratified approach to earlier diagnosis of cancer
Funder: Cancer Research UK

Abstract: Background: Cancer prevention and control strategies increasingly focus on the earlier diagnosis of symptomatic patients. How to achieve the full potential benefits of earlier diagnosis is nevertheless uncertain. Recent evidence indicates the importance of understanding how the risk of late diagnosis varies between patients with different cancers and characteristics. Aim: To generate evidence to help stratify (target and tailor) early diagnosis research and policies, increasing their effectiveness. Methods: The proposed research is motivated by a conceptual framework that jointly considers interval and outcome measures of early diagnosis (the former encompass patient, primary care, and system (hospital) intervals; the latter include stage at diagnosis and emergency diagnosis of cancer). It will use cancer registration data of increasing quality and completeness and other ad hoc or linked healthcare datasets. It will also develop and validate new methods for measuring the primary care interval using primary care electronic health records. Work streams will examine variation in: • The patient interval by symptom status. • The primary care interval, particularly regarding variation by ethnic group. • The system (post-referral, hospital) interval, focusing on patients at higher risk of inadvertent misclassification of initially suspected cancer due to shared symptoms. • The distribution of stage at diagnosis, by socio-demographic group. For cancers subject to awareness or screening interventions (e.g. breast, colorectal, melanoma) time trends in stage at diagnosis will also be examined (pre/post-NAEDI). Further work streams will: • Develop methods to describe the pre-diagnosis care experience of cancer patients who are diagnosed as emergencies, using information on their complete care pathway across the primary / secondary care divide. • Explore mechanisms potentially responsible for patient (pre-presentation) delay, particularly regarding age inequalities in the stage at diagnosis of breast cancer. How the results of this research will be used: The findings will allow the targeting of public health and healthcare early diagnosis interventions. For example, they will inform the nature and focus of Be Clear on Cancer awareness campaigns and the design of healthcare interventions to support decision-making by general practitioners. In addition, the project will develop methods that will improve the population-based monitoring of early diagnosis measures in the future. A stratified approach to the development of early diagnosis interventions can help to greatly improve their effectiveness, producing sustainable health benefits for future generations of cancer patients.


Research activity codes: 8.2 HEALTH AND WELFARE ECONOMICS;4.3 INFLUENCES AND IMPACT;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Understanding how membrane transporters influence variability in cancer drug uptake and investigating implications for efficacy
Funder: Cancer Research UK

Abstract: Background: For a drug to effectively engage its intended target, it must be present at the correct concentration. In tumours, poor vascularity impacts drug availability. However, once at the tumour site, how drugs enter cancer cells is often overlooked. Drug development has aimed to optimise lipophilicity of compounds to ensure cell-permeability, but increasing evidence suggests that membrane transporters also play an important role in drug uptake. In their endogenous role, transporters regulate the passage of metabolites across biological membranes and in cancer, their expression patterns are highly heterogeneous. Heterogeneity in transporter expression may play a role in patient-to-patient differences in chemotherapeutic response. This work aims to investigate the inter-tumour heterogeneity of drug uptake, to understand the role that membrane transporters play in this variability, and to investigate how this affects drug efficacy. Aims: 1. Determine variability in absolute intracellular drug concentrations in cancer cells 2. Identify the molecular determinants of intracellular drug concentration 3. Investigate the implications of differential drug uptake on compound efficacy Methods: We will use a high-throughput mass spectrometry pipeline to measure intracellular concentrations of chemically diverse anti-neoplastic compounds. Integrating -omics datasets, we will identify the strongest molecular determinants of drug uptake before validating these predicted interactions using protein over-expression and knock-down. We will explore the implications of heterogeneity in drug uptake for drug efficacy, at both the population (proteomics/phospho-proteomics) and single-cell level (high-content imaging). Additionally, we will investigate primary ovarian cancer samples to determine whether transporter expression or activity influence therapeutic response and/or resistance. Our novel, unbiased approach will explore the variability of drug uptake in cancer and determine the extent of the role of transporters versus other molecular determinants, such as lipids, in this diversity. How the results of this research will be used: The newly-identified drug-transporter interactions could provide functional biomarkers for compound efficacy and help to stratify patients for clinical trial. Our studies of primary ovarian cancer samples will provide insight into the heterogeneity of drug uptake clinically, potentially uncovering previously-unknown mechanisms of drug resistance.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Deciphering the processes driving metastatic disease and death in lung cancer
Funder: Cancer Research UK

Abstract: Background There are numerous ways in which cancers are thought to lead to death and whilst many studies have highlighted processes contributing to metastatic disease, we lack a unified understanding of how metastatic disease impacts the host and ultimately results in death. This proposal takes a broad approach incorporating the patient and the disease, as well as the multiple facets of tumour evolution, to begin to understand the aetiology of death in patients with lung cancer in a real-world NHS setting. Aims The aim of this proposal is to demonstrate that the mechanism(s) contributing to death in lung cancer include the following: • Rapid tumour dissemination and increasing genomic instability • Metabolic disturbance mediated by catabolic factors and pro-inflammatory cytokines • Failure of the adaptive immune system otherwise capable of restraining tumour evolution Methods Using novel analytical approaches, incorporating detailed radiological mapping of tumour dissemination, DNA, RNA and tumour microenvironment analyses, primary and metastatic tissue within the TRACERx lung and PEACE autopsy studies will be analysed in order to meticulously trace the clinical disease course in the context of genomic, metabolic, immune and physiological studies to inform our understanding of how and why patients die of lung cancer, and to identify the features and behaviour of aggressive cancers destined to metastasise. How the results of this research will be used The scientific and clinical need to understand the biology of metastatic disease and the underlying mechanisms leading to death in lung cancer is strikingly evident given the incidence and mortality rates worldwide. Investigating the genomic, metabolic and immune processes involved may elucidate novel therapeutic opportunities and inform future patient care pathways.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/15/074 ICON9: An international phase 3 randomised trial of cediranib and olaparib maintenance in patients with relapsed platinum sensitive ovarian cancer
Funder: Cancer Research UK

Abstract: Background Ovarian cancer is the fifth commonest malignancy in UK and represents the commonest cause of death from gynaecologic malignancy. Despite significant improvements in treatment, the majority of of women diagnosed with ovarian malignancy will ultimately relapse and die from their disease. Patients relapsing more than six months after completion of therapy have a median survival of about 2.5 years, clinical trials with novel agents are therefore highly justified and address an unmet need. Cediranib, a potent small-molecule inhibitor of VEGFR-1/2/3, has a 19% single agent response rate in recurrent ovarian cancer, which is similar to the monoclonal antibody, bevacizumab. The ICON6 trial demonstrated that the combination of cediranib and chemotherapy followed by continuous (maintenance) cediranib led to an overall survival benefit of 2.7 months and an increased time to progression of 3.2 months in patients with relapsed platinum sensitive ovarian cancer. Preclinical studies indicate that tumour cells exposed to chronic hypoxia acquire defects in DNA repair resulting in increased sensitivity to PARP inhibition. Therefore the direct targeting of PARP by olaparib and indirect sensitisation to olaparib by acquisition of DNA repair defects by cediranib may be therapeutically beneficial and applicable to a wider population of non BRCA mutated patients with ovarian cancer. Benefit from this combination was demonstrated in a recent phase 2 trial in patients with relapsed platinum-sensitive ovarian cancer. There was a significant improvement in progression free survival (PFS) in the group receiving combination cediranib and olaparib compared to olaparib treatment alone. The combination was tolerable, and some patients remained on treatment for over a year suggesting that this would be a reasonable regimen to consider in the maintenance setting. Aims To investigate the efficacy and safety of maintenance treatment with cediranib and olaparib compared to single agent cediranib, as measured by PFS and overall survival (OS), in patients with relapsed platinum sensitive ovarian cancer. Methods An international phase III trial for 615 patients with epithelial ovarian, fallopian tube or primary serous peritoneal carcinoma who require platinum-based chemotherapy for relapse 6 months after the last dose of first-line chemotherapy. Patients will receive a combination of chemotherapy and cediranib followed by maintenance treatment with either cediranib alone or a combination of olaparib and cediranib until disease progression. Results The results will inform future clinical practice in the treatment of patients with relapsed ovarian cancer.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/19/015 VALTIVE1: Validation of Tie2 as the first tumour vascular response biomarker for VEGF inhibitors: Optimising the design of a subsequent randomised discontinuation trial
Funder: Cancer Research UK

Abstract: Validation of Tie2 for VEGF inhibitors: VALTIVE1 Abstract Background Anti-angiogenic, VEGF inhibitors (VEGFi) increase progression free survival (PFS) and, in some cases, overall survival in many solid tumours. However, their use has been compromised by a lack of informative biomarkers. We have shown that plasma Tie2 is the first tumour vascular response biomarker for VEGFi in ovarian, colorectal and gall bladder cancer: If plasma Tie2 concentrations do not change after 9 weeks of treatment with a VEGFi the patient does not benefit, whereas a confirmed reduction of at least 10% plasma Tie2 defines a vascular response with an HR for PFS of 0.56. Aims We aim to complete the CRUK biomarker roadmap so that Tie2 can be deployed in the NHS for clinical decision making over the use of VEGFi. This will be achieved through validation of Tie2-defined vascular response criteria in ovarian cancer. Secondary aims include: validation of Tie2-defined vascular progression criteria; establishment of the Tie2 ELISA at NHS standards with real time reporting; and optimisation of sample timing and analytical algorithms. Methods VALTIVE1: We will recruit 176 patients with ovarian cancer who are receiving first line platinum-based chemotherapy and bevacizumab, in keeping with NHS/Cancer Drugs Fund criteria. The patients’ management will not be changed. Plasma samples will be taken before and during bevacizumab and upon disease progression. The PFS (primary endpoint) of Tie2-defined vascular non-responders and responders will be compared. How the results of this research will be used VALTIVE2: The purpose of VALTIVE1 is to optimise sample acquisition time points and analytical algorithms to support the design of VALTIVE2; a randomised discontinuation trial. In VALTIVE2, Tie2-defined, vascular non-responding patients will be randomly allocated to stop bevacizumab after 9 weeks, by when a response can be detected, or to continue bevacizumab for the conventional year of treatment. The hypothesis is that early discontinuation will not disadvantage the patients. This randomised clinical trial will complete the CRUK biomarker roadmap. In addition to the reduction in toxicity and cost for Tie2 non-responders, and the rationale for extending first line bevacizumab in Tie2-defined long term responders, the programme is important for ovarian cancer as we know that (i) reuse of bevacizumab is effective, (ii) we need to distinguish which patients should receive VEGFi or PARPi and (iii) because new combinations of VEGFi with PARPi or immune checkpoint inhibitors are in development. Biomarkers to optimise use of these combinations are critical.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS