NIHRDataInsights/HRCSData huggingface dataset:
Title: SERIAL ARTIFICIAL INTELLIGENCE/MACHINE LEARNING CLASSIFIERS FOR PERSONALISED RISK STRATIFICATION AND EARLY DETECTION OF LUNG, BOWEL AND PANCREATIC CANCERS IN WOMEN (SAICRED)
Funder: Cancer Research UK

Abstract: Background: Early detection of cancer is critical to improving outcome and use of blood-borne biomarkers holds promise for early detection through screening or when incorporated early into diagnostic pathways for at-risk patients. Despite this, the current best markers lack the desired performance as standalone early detection tests and improvements in diagnostic accuracy and lead time are urgently needed. Most early detection studies have only included analysis of single samples and have not considered serial samples where deviations from an individual’s baseline can improve performance. Novel methods of combining analyte data and risk factors applied to newly generated longitudinal data may improve performance. Aims: Our overall aim is to develop more effective blood tests for early detection of lung (NSCLC), colorectal (CRC) and pancreatic (PC) cancers. The work builds on our finding that combining markers into longitudinal and/or network models improves classification of prediagnosis samples sourced from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). We will develop a novel methodology based on comprehensive systems of multiple classifiers (SMC) to analyse serial high-dimensional data, which would be able to detect each of the three cancers at a stage when death can be prevented. Through analysis of longitudinal data that has never before been available, this will deliver a fundamentally new approach to the problem of early detection of cancer. Methods: To develop effective serial classifiers, we will use biomarker datasets for a subset of women recruited to the UKCTOCS. The SMC will build on four different Artificial Intelligence (AI) and Machine Learning (ML) approaches to whose development we have contributed: Deep Learning, Method of Mean Trends, Bayesian change-point model, and parenclitic networks. To successfully deliver the stated aim of this Project, we will develop new approaches suitable for analysis of longitudinal high-dimensional data. New methodologies for combining classifiers into ensembles will also be tested, and a clinical decision support system with user interface will be developed to provide tools for early detection of each cancer type. How the results of this research will be used: We anticipate that findings from this project will support prospective clinical trials to demonstrate the mortality benefit of using these non-invasive early detection blood tests, particularly in combination with other screening modalities and in high-risk populations. It is hoped that this methodology will form an integral part of standardised screening/surveillance programs by delivering a step-change in personalised early detection of high mortality cancers.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Novel image-guided therapeutics to improve surgical precision and loco-regional control in Neuroblastoma.
Funder: Wellcome Trust

Abstract: Neuroblastoma (NB) is the most common extra-cranial solid cancer in children and contributes to 15% of childhood cancer deaths. Surgery to remove NB is often incomplete and poses high risks due to the significant involvement of vital organs and vessels.We aim to develop a novel integrated surgical platform to eliminate cancer more efficiently and safely. With the synergistic use of highly innovative optical techniques, built around a core technology of using injectable probes, we aim to:1. Specifically, “light up” cancer to help the surgeon in differentiating tumour from vital organs (colour-coded surgery).2. Equip the surgeon with an innovative special scanner to chase small and non-visible cancer residuals.3. Kill any minimal residual cancer, left by the surgeon, using a new technology based on light.This original approach has the potential to improve the effectiveness of surgery in eradicating solid paediatric and adult cancers, leading to better survival and fewer complications.

Lay abstract: Neuroblastoma (NB) is the most common extra-cranial solid cancer in children and contributes to 15% of childhood cancer deaths. Surgery to remove NB is often incomplete and poses high risks due to the significant involvement of vital organs and vessels.We aim to develop a novel integrated surgical platform to eliminate cancer more efficiently and safely. With the synergistic use of highly innovative optical techniques, built around a core technology of using injectable probes, we aim to: 1. Specifically, “light up” cancer to help the surgeon in differentiating tumour from vital organs (colour-coded surgery). 2. Equip the surgeon with an innovative special scanner to chase small and non-visible cancer residuals. 3. Kill any minimal residual cancer, left by the surgeon, using a new technology based on light. This original approach has the potential to improve the effectiveness of surgery in eradicating solid paediatric and adult cancers, leading to better survival and fewer complications.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Improving the early detection of lung cancer by combining exosomal analysis of hypoxia with standard of care imaging
Funder: Cancer Research UK

Abstract: Background In cancer, intratumoural hypoxia is associated with an increased risk of invasion, metastasis, therapy resistance, and a worse clinical prognosis. The collagen prolyl-4-hydroxylase (P4HA)1 is induced by hypoxia through the hypoxia-response element (HRE) present in its gene promoter. In preclinical studies, hypoxia sensing has been used successfully to detect relatively small volumes of cancer cells. We have recently developed a novel serum exosomal assay based on detection of hypoxia, by measuring P4HA1 (which was shown in both colorectal and lung cancer patients to be inversely correlated with an imaging parameter that measures the degree of tissue perfusion by CT). Further we have shown that a distinct set of exosomal proteins, namely, HER2, HER3 and S100A9, which are linked to increased tumour aggressiveness, were elevated in ‘P4HA1 positive’ lung cancer patients. Aims We will expand this serum exosomal assay by integrating with the assessment of pre-microRNA processing, as well as our recently published hypoxia gene signature in exosomes. We will perform these exosomal assays in order to obtain a multimodality risk signature that can be applied to individuals suspected to have lung cancer, within a defined clinical diagnostic pathway. In addition, we will optimise the combination use of these exosomal assays with CT imaging-derived parameters (perfusion-based and radiomic analyses), in order to improve on the current accuracy of lung cancer detection, especially that of more aggressive disease at an early stage of diagnosis. Methods We will carry out a prospective cohort study of patients referred to secondary care for the investigation of clinical symptoms or signs suspicious of lung cancer. The study setting will be East and North Hertfordshire NHS Trust (population catchment area of 600,000) and include patients who have been referred to the Lung Cancer Clinic and Multi-Disciplinary Team (MDT) for investigation of suspected lung cancer. How the results of this research will be used. Having established that our blood exosomal test can detect clinical lung cancer at the time of imaging and interval cancers during subsequent follow up; we will expand the study to establish the sensitivity/specificity data for the ‘combined CT/exosomal risk stratification’ model. We aim to improve the accuracy of detection and/or prediction of future disease by performing the combined imaging-exosome test. This will move towards the identification of blood tests can help increase confidence about follow-up decisions and shorten the interval before biopsy.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Barts ECMC core funding to cover both core services required for both the clinical trials unit and the Cancer Research Delivery Group.
Funder: Cancer Research UK

Abstract: Barts ECMC core funding to cover both core services required for both the clinical trials unit and the Cancer Research Delivery Group.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: CRUK/13/010:UNIRAD Randomised double-blind phase III trial evaluating the safety and benefit of adding everolimus to adjuvant HT in women with poor prognosis ER+ and HER2- primary breast cancer who remain free of disease after receiving at least 1 year of adjuvant HT
Funder: Cancer Research UK

Abstract: Background Although remarkable progress has been made in the adjuvant treatment of breast cancer, a significant number of patients ER positive disease are at risk of relapse. This is particularly true in patients with extensive lymph node involvement (4N+) at diagnosis. There is therefore an unmet clinical need for the treatment of patients presenting with high risk ER positive breast cancer defined by significant lymph node involvement or residual nodal involvement after neoadjuvant chemotherapy. A new class of agents, mTOR inhibitors, provide a novel approach to countering the potential acquired resistance to endocrine therapy. Aims The UNIRAD study will investigate whether the addition of everolimus to standard adjuvant endocrine therapy can decrease the rate of disease relapse in patients with ER positive, HER2 negative breast cancer who have received approximately 3 years of standard care endocrine therapy. Methods UNIRAD is a double-blind, multicentre, phase III randomized trial of patients with poor prognosis (4+ involved lymph nodes at the time of diagnosis) ER+ and HER2- primary, non-metastatic breast cancer, who remain disease-free after 3 years of adjuvant endocrine therapy. The trial has been developed by the French UNICANCER group, and the trial is expected to open to recruitment in early 2013 in France. Eligible patients will be randomised 1:1 to receive either: everolimus (10mg/day) added to standard care endocrine therapy or placebo (2 tablets/day) added to standard care endocrine therapy. In both groups, treatment will continue for the remainder of the 5 years endocrine treatment period (maximum 2 years everolimus treatment). The total sample size will be 1984 patients, recruited from France, Belgium and the UK. Approximately 23 UK hospitals will participate aiming to contribute approximately 300 patients. Diagnostic, archive tissue samples will be collected from all participating patients for correlative science studies to investigate the prognostic and predictive value of subgroups based on IHC markers of mTOR activation and on mutational analysis of PI3K/AKT. In the UK, an additional correlative science sub-study is planned to investigate the predictive and prognostic value of cell free DNA via collection of lymph node tissue samples and blood samples at baseline, 4 months, 12 months and 24 months. How results will be used Results will provide an evidence base for the use of everolimus in the treatment of ER positive, HER2 negative early breast cancer at high risk of relapse. Favourable results could lead to a change in practice.


Research activity codes: 6.1 PHARMACEUTICALS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: A Case Control Study of women aged 30-39 to augment breast cancer risk prediction and assess acceptability and preference of a systematic risk prediction approach through primary care.
Funder: Cancer Research UK

Abstract: Breast cancer (BC) is the most common cause of death in women aged 30-39. In most health systems BC family history (FH) is the only risk factor routinely used to identify young women at increased risk. However, most affected women do not have a BC FH. Risk algorithms incorporating lifestyle/reproductive risk factors, mammographic density (MD) and polygenic risk scores (PRS)have been developed but are limited by the lack of MD data in this age group. We have developed automated low dose risk assessment mammography (ALDRAM) to assess MD in young women and will conduct a case control study in an ethnically and socioeconomically diverse population of women aged 30-39 with the aims of augmenting risk algorithms and improving reach of risk assessment. 250 cases will complete risk factor questionnaire (RFQ) and saliva sample for PRS (SNP313). 750 controls, without BC FH, will be recruited from primary care and invited to undergo RFQ, PRS and ALDRAM for MD in a single appointment. MD and ethnicity tailored PRS will be incorporated into BOADICEA and Tyrer-Cuzick algorithms and BC risk fed back. Those at increased risk will be offered expert review, enhanced screening and prevention strategies. Acceptability of methods of approach and feedback will be assessed and a patient preference survey across diverse US and UK populations will inform subsequent economic analyses. A sub-study of cervical self-sampling will evaluate our DNA methylation signatures of breast cancer risk with the goal of further improving risk algorithms.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Tumour Microenvironment and Proteomics
Funder: Cancer Research UK

Abstract: The tumour stroma is composed of many different cell types and extracellular matrix components that work in concert to generate a microenvironment permissive to tumour initiation, progression and metastasis. Cancer associated fibroblasts (CAFs) are a major non-neoplastic cell type in solid tumours. They are characterised by the ability to secrete a plethora of factors and establish physical interactions with the surrounding cells, including endothelial, cancer and immune cells. This results in CAFs being key players in cancer pathology through creating an aberrant tumour microenvironment and altering the behaviour of the surrounding cells. For this reason, CAFs are considered a promising target for therapy. Our research is focused on identifying how to exploit CAFs to effectively target tumours, primarily breast and ovarian cancers. In particular, we are studying the dynamic interactions that CAFs establish with cancer cells and endothelial cells to identify: CAF pathways fundamental to support their pro-invasive/tumourigenic functions; CAF-endothelial cell interactions that promote blood vessel remodelling and metastasis; and CAF-cancer cell interactions upon which cancer cells are critically vulnerable. To achieve this, our group exploits and develops in vitro and in vivo models that we investigate using a unique combination of cell and molecular biology approaches, together with state-of-the-art quantitative mass spectrometry-based proteomics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Immune Priming and the Tumour Microenvironment
Funder: Cancer Research UK

Abstract: Tumour immunotherapy, most notably checkpoint blockade therapy, has produced remarkable benefits for patients with cancers that previously had poor outcomes. Blockade of the T cell inhibitory checkpoint molecules CTLA-4 and PD-1 has led to dramatic remissions that have lasted more than a decade in many patients. However, these responses are unfortunately restricted to only a subset of patients. Our work broadly aims to understand how the immune response to cancer is generated so as to understand what may limit the quality or quantity of that response. In this way, we hope to find new means of augmenting the response to immunotherapy in a broader subset of patients. To do this, we are focusing on how the T-cell-mediated immune response is initiated. T cell responses begin in the lymph node, where they are directed by signals received from the peripheral tissue, where the challenge occurs. During responses to viruses, numerous signals drive re-organisation of the lymph node and choreograph a highly regulated process by which appropriate T cell activation can occur. It has been observed that the tumour-draining lymph node is improperly activated, suggesting priming may be less efficient against the tumour. Indeed vaccination, which improves priming, can improve immunotherapeutic approaches in mice, suggesting this as a viable approach. As such, our aim is to determine how the periphery communicates with and educates the lymph node during an efficient immune response and how this is subverted in the tumour setting. Of particular interest to us is the role of different dendritic cell subsets in organising and directing efficient immune responses in the lymph node, and how these are manipulated by the tumour microenvironment. In this way, we aim to discover signals by which we can convert the lymph node microenvironment into a more effective site of immune priming to augment existing immunotherapeutic responses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Migration, Invasion and Metastasis
Funder: Cancer Research UK

Abstract: Background We are interested in how cells move during embryo development and in cancer and the parallels between these two processes. Tumours are chaotic and frequently they select for elements of a reversion to developmental programmes, as the tumour struggles to overcome challenges such as nutrient and oxygen deprivation. Our research programme addresses cell migration and cancer metastasis at different levels, from fundamental molecular mechanisms to specific developmental and cancer models. Molecularly, we focus on actin nucleation and its control by the Rho-family of GTPases. We apply this molecular research to study melanocytes, melanoma and pancreatic cancer as examples of highly motile cells and cancers with unmet need. Aims: We seek to answer a number of fundamental questions about how the actin nucleation machinery drives cell migration and is used by tumour cells during progression and metastasis. •How does the cell mobilise the pentameric Scar/WAVE Regulatory Complex and how is it regulated by Rac1 and other motility signals? •How do melanoblasts migrate and what drives their journey through the developing embryo? •How is the Rac1 – Scar/WAVE Complex – Arp2/3 pathway used in melanoma progression and metastasis? •How are the Scar/WAVE Complex and other actin nucleating proteins mobilised during the progression of pancreatic cancer and in metastasis? Methods: We use molecular cell biology to study basic mechanisms of how cells migrate in reconstituted environments, such as 3D matrix and engineered surfaces. We also grow primary cells from mouse models to form organoids and to recreate tumour growth and invasion. We use mouse genetic models of development, melanoma and pancreatic cancer to model migration, progression and metastasis in vivo. We work with clinicians to relate our studies to human disease. How the results of this research will be used: Targets that we identify from this research programme will be pursued with Beatson Drug Discovery and by collaboration with clinician scientists and Cancer Research Technology to relate our findings in models to human patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: PATHOS -T: A Bioresource Collection associated with PATHOS, a Phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV)-positive oropharyngeal cancer
Funder: Cancer Research UK

Abstract: Background PATHOS is a CRUK-funded randomised controlled trial currently recruiting to target in 31 UK sites and about to open across three continents, investigating the potential of Transoral Surgery and Neck Dissection, followed by risk-stratified, reduced intensity adjuvant treatment, to reduce late toxicity rates, whilst maintaining high survival rates, in patients with Human papillomavirus (HPV)-positive oropharyngeal cancer (HPV+OPSCC). Surgery allows the collection of primary tumour and lymph node biopsies which, together with serial blood samples, provide a unique bioresource collection (PATHOS-T). PATHOS transitioned from phase II to III in Oct 2018 and this bid seeks support to extend the PATHOS-T bioresource collection for the duration of the phase III trial (target 1100 patients, end date 2022). This will be the largest HPV+OPSCC bioresource collection in the world and the samples collected are of extremely high quality and will underpin a future translational programme of research (PATHOS-Trans). Aims To gain a deeper understanding of the biological differences between patients who respond to treatment compared with those that do not. We will also define molecular signatures that will discriminate non-responders and responders and define biological targets against which novel therapeutic strategies can be directed. Methods PATHOS-T includes collection of: Up to 5 primary tumour and 2 lymph node biopsies and blood samples at baseline and at 5 post-treatment time-points. To date, 726 tissue samples and 1262 blood samples have been collected from 203 patients. Patient acceptability rate is high (96%) and DNA and RNA quality has been assured. By the end of the phase III, ~ 3250 blood samples, ~1400 tissue samples and ~30 tissue samples taken from recurrent tumour will be collected. How the results of this research will be used PATHOS, PATHOS-T and PATHOS-Trans provide a unique, world-leading opportunity to change treatment paradigms for patients with HPV+OPSCC globally. By identifying novel targets for immunotherapy and patients at high risk of relapse at diagnosis, after surgery and after adjuvant treatment we will be able to personalise the use of adjuvant treatment and intervene earlier, with novel immunotherapeutic based strategies, to cure recurrence. More generally, this suite of studies will accelerate the implementation of genomic- based precision medicine into routine clinical practice in keeping with the high-level strategic objectives of NHS England.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS