NIHRDataInsights/HRCSData huggingface dataset:
Title: eDyNAmiC (extrachromosomal DNA in Cancer) – Understanding the biology of ecDNA generation and action, and developing new ways to target these mechanisms in cancer
Funder: Cancer Research UK

Abstract: Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumour-promoting genes can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). These ecDNA do not follow the normal “rules” of chromosomal inheritance, enabling tumours to achieve far higher levels of cancer-causing oncogenes than would otherwise be possible, and licensing cancers with a way to evolve and change their genomes to evade treatments at rates that would be unthinkable for human cells. The altered circular architecture of ecDNAs also changes the way that the cancer-causing genes are regulated and expressed, further contributing to aggressive tumour growth. These unique features make ecDNA-containing cancers especially aggressive and difficult to treat. Cancer patients whose tumours harbour ecDNA have markedly shorter survival. Despite being first seen over fifty years ago, the critical importance of ecDNA has only recently come to light, and the scale of the problem is substantial. ecDNAs are present in nearly half of all human cancer types and up-to a third of all cancer patients. The collective current understanding of how ecDNA form, how they function, how they move around the cell, how they evolve to resist treatment, how they impact the immune system, and how they can be effectively targeted are lacking. We bring together an internationally recognized, pioneering interdisciplinary team of cancer biologists, geneticists, computer scientists, evolutionary biologists, mathematicians, clinicians, and patient advocates to boldly create novel insights and resources and to provide transformative solutions to one of Cancer’s Grand Challenges. A core team of experienced and productive ecDNA investigators will work with new investigators in the ecDNA and cancer fields to bring completely new perspectives and approaches to this daunting challenge. By bridging cutting-edge and diverse approaches and insights from cancer genomics, yeast genetics, epigenomics, artificial genome synthesis, longitudinal patient tracking, combinatorial and machine learning algorithms, mathematical modelling, immunobiology, and innovative chemistry we will develop a new understanding of the role of ecDNA in cancer, and we will find new ways to drug the undruggable. This bold programme, which consists of 7 work packages and a committed international infrastructure, generates new and unusual collaborations that would simply be impossible under any other type of funding mechanism. Our programme endeavours to foster bold innovative solutions to one of the hardest problems in cancer and to one of the greatest challenges facing cancer patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The identification of patients who benefit from novel immune therapies.
Funder: Barts Charity

Abstract: A novel wave of immune therapies are changing the way cancer is treated. They are known as immune checkpoint inhibitors. Not all patients benefit from therapy especially those with advanced metastatic disease. Barts has helped develop a number of these agents. This grant focuses on funding core parts of this group to deliver key experiments over the next 5 years. We have obtained sequential tissue from bladder cancers before and after 6 weeks of immune checkpoint therapy to look for dynamic changes to molecular parameters associated with response and resistance to therapy. We are also performing projects on new aspects of the immune system to look for new combinations in the future. Together, this project will lead to better personalised care for patients in the future. It will also underpin the structure of the research group for the next 5 years.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: A single cell mRNA atlas of rhabdomyosarcoma at presentation and relapse - identifying foetal developmental targets (co-funded by Children with Cancer UK)
Funder: Cancer Research UK

Abstract: BACKGROUND Following dramatic improvement in the outlook of children suffering from RMS in the 1970s and 1980s, progress has stalled since, in spite of extensive clinical and biological research. Therefore, it would appear unlikely that the prognosis of children with RMS will improve significantly by variations of “more of the same”. One aspect of RMS biology that remains relatively unexplored is the foetal root of RMS. RMS is thought to form from foetal mesenchymal cells that differentiate aberrantly along a trajectory of striated muscle cells. We speculate that within these trajectories of aberrant development lie novel therapeutic opportunities. At its simplest, there may be transcripts that are exclusive to the foetal period, yet persist in RMS and thus represent formidable targets for chemical compounds or immune therapy approaches. Or, more fundamentally, we may be able to predict what transcriptional states we require, to induce therapeutic maturation of cancer cells. AIMS Our aim is to build a developmental single cell atlas of rhabdomyosarcoma (RMS) at diagnosis and relapse, in order to identify foetal developmental targets. We will profile single RMS cell transcriptomes in relation to differentiation of normal foetal cells and to RMS models of maturation, resistance and relapse. METHODS To build the atlas we will: (i) Profile 250,000 RMS cells obtained from 50 fresh tumour specimens at diagnosis and relapse, using single cell mRNA sequencing (Chromium10x platform), integrated with bulk mRNA and DNA data. (ii) We will validate and spatially locate RMS cell types using multiplexed single molecule FISH and immunohistochemistry. (iii) Our data analyses will aim to elucidate treatment targets, esp. mRNA states of maturing RMS cells. In in vitro models of RMS we will perform pertubation experiments to: (i) study the transcription underpinning RMS maturation, resistance and metastases (ii) to provide proof-of-principle validation of manipulating developmental trajectories. HOW THE RESULTS OF THIS RESEARCH WILL BE USED We envision that our results will provide novel mechanistic and therapeutic hypotheses. We may then be able to pursue these in follow-up studies, including dedicated translational efforts. Moreover, as we will make our data freely available, we will provide what will hopefully be a transformational data resource for the RMS research community. Finally, our approach to study the foetal roots of RMS may define a blue print for similar enquiries into other childhood tumours.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Birmingham ECMC
Funder: Cancer Research UK

Abstract: Birmingham ECMC accelerates translation of discovery science into the clinic, by promoting rational development/application of novel therapies, providing clinical networks for their evaluation, and supplying linked patient data/samples for future development. Translational efforts relate to (i) new therapeutic concepts emanating from Centre research, such as our EBV Vaccine programme; (ii) novel targeted therapy trials such as National Lung Matrix (currently being integrated across the ECMC network); and (iii) reverse translational approaches, capitalising on UoB’s key role in the 100,000 Genome Project by providing an integrated biosample/data collection platform linking 18 regional hospitals. The predominant focus for the ECMC going forward will be on innovatively-designed Phase 1/2 trials, recruiting stratified patient cohorts, seeking robust therapeutic signals capable of transforming patient outcomes, and also integration with optimised surgical approaches. This synergises with CRCTU’s expertise and strategic aims, including efficient trial design (eg adaptive/multi-arm/multi-stage) and novel window-of-opportunity studies. We will focus predominantly on established clinical strengths in colorectal cancer, head and neck cancer, lung cancer, and haematological malignancies, increasing the speed and efficiency of the translation of fundamental research.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION)
Health categories: CANCER AND NEOPLASMS
Title: Cambridge ECMC
Funder: Cancer Research UK

Abstract: The Cambridge ECMC enables the translation of discoveries made by Cambridge science into patient benefit, by underpinning all the clinical research activity at the CRUK Cambridge Centre. The Cambridge ECMC will focus on three strategic objectives: We will translate biological discoveries into effective new cancer therapies: ECMC funding will be used to support key elements of our clinical research management team, working with the CRUK Cambridge Centre Programmes to design and deliver innovative clinical trials, locally and across the ECMC-Network, thereby addressing the ECMC Network’s aims to: • ‘Drive the design and delivery of translational studies and scientifically driven, rationally designed early phase oncology trials to the highest international quality.’ • ‘Ensure effective joint working across the Network and between Universities and Trusts.’ • ‘Ensure that the UK remains at the forefront of international efforts to develop and test new treatments for cancer, built upon outstanding science and optimal trial design.’ • ‘Increase the attractiveness of the UK as the industry’s destination of choice for the development of high impact, innovative treatments, and thereby contribute to economic growth.’ We will invent and implement new devices and biomarkers capable of detecting cancer early and monitoring cancer progression and treatment response: We will apply Cambridge’s discoveries in advanced imaging and ‘liquid biopsy’ research to prospectively treated patients in clinical trials. To do this we will invest ECMC funds in the conduct of translational cancer imaging and ‘liquid biopsy’ research, thereby addressing the ECMC Network’s aims to: • ‘Maximise therapeutic opportunities for patients through the development and validation of novel molecular and/or imaging biomarker assays to regulatory standards.’ We will promote patient and public involvement in experimental cancer medicine: We will leverage the Administration and Outreach Shared Infrastructure-Resource in the CRUK Cambridge Centre to meet the ECMC Network’s aims to: • ‘Promote patient and public involvement in experimental cancer medicine.’


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS
Title: Developing novel targeted immunotherapy for infant and childhood MLL-rearranged acute lymphoblastic leukaemia (co-funded by Children with Cancer UK)
Funder: Cancer Research UK

Abstract: Background: MLL-rearranged infant acute lymphoblastic leukaemia (MLLr-iALL) has a very poor prognosis (40% cure rates), highlighting the need for novel treatment strategies. Chimaeric antigen receptor (CAR)-based immunotherapy in the form of CAR-T-cells directed against antigens that are expressed on the surface of leukaemic cells (CD19/CD22) is the most recent novel therapy against childhood ALL. A limitation to CAR-T therapy for iALL is the need for autologous T-cells, often difficult to obtain reliably from such young children after intensive chemotherapy. CAR-invariant natural killer T (CAR-iNKT) cell immunotherapy is an attractive alternative approach because of their potential for ‘off-the-shelf’ availability and superior performance compared to CAR-T therapy in preclinical CD19+ lymphoma. In this project, we aim to design and validate bispecific iNKT-cell immunotherapy against CD19 and CD133 antigens expressed on MLLr leukaemic cells. Aims and methods: 1. Define the pattern of co-expression of CD19, CD133 and CD1d surface antigens on normal fetal and paediatric haematopoietic stem and progenitor cells (HSPC) and MLLr-ALL blasts using multiparameter flow cytometry. 2. Develop and validate anti-CD133 CAR iNKT-cell immunotherapy by developing first a lentiviral CAR133 followed by generation of CAR-iNKT-cells using optimised protocols. Efficacy of CAR133-iNKT-cells will be validated using in vitro and in vivo assays against MLLr cell lines, MLLr ALL patient samples and a novel MLL-AF4 leukaemia in vivo model and compared to CAR133-T cells. The functional profile of anti-leukaemic CAR133-iNKT-cells will be studied using the Chromium 10x platform to simultaneously analyse transcriptome and TCR repertoire in single CAR-iNKT-cells; and imaging mass cytometry to investigate the spatial relationship between tissue resident CAR-iNKT-cells and leukaemic cells. 3. Develop and validate optimal bi-specific CAR19/133-iNKT immunotherapy by combining the optimal CAR133 developed in (2) with CAR19 to generate bispecific CAR19/133-iNKT-cells. The efficacy of these cells will be validated as in (2) and compared to monospecific CAR19-iNKT and CAR133-iNKT-cells. 4. Determine whether CAR CD19/133 -iNKT cells cause major haematological toxicity (given CD133 expression on a wide range of normal HSPC) using in vivo models of humanised haematopoiesis. Expected impact: Bispecific CAR19/133-iNKT cell immunotherapy will be an effective ‘off-the-shelf’ treatment for MLLr-ALL. We envisage that upon completion of this project, we will be able to swiftly proceed to clinical development. This novel immunotherapy will allow us to deliver clinically meaningful improvements in outcome for infant ALL, which so far has been impossible to achieve.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/14/017: Neo-AEGIS - Randomised Clinical Trial of neoadjuvant and adjuvant chemotherapy (MAGIC regimen) vs. neoadjuvant chemoradiation (CROSS protocol) in adenocarcinoma of the oesophagus and oesophago-gastric junction
Funder: Cancer Research UK

Abstract: Background: Adenocarcinoma of the oesophagus and oesophagastric junction have increased in incidence in the West over the last quarter century. Oesophageal cancer is now the 9th most common cancer in the UK, accounting for 3% of all new cases. In 2010, there were 8,477 new cases of oesophageal cancer in the UK. The neo-AEGIS trial will compare 2 established regimens that have been previously tested within randomised studies, specifically the MAGIC regimen, initially designed for gastric cancer and increasingly applied to junctional tumours, and the recently reported CROSS trial. Gaps currently exist in the evidence-base with respect to the optimal approach to treatment for adenocarcinoma of the oesophagus and junction to justify this comparison, and in particular this study will address the added value if any of radiation therapy. Aims: Primary Objective: To evaluate one, two and three year overall survival of oesophageal patients treated with resection plus neoadjuvant and adjuvant chemotherapy versus resection plus neoadjuvant chemo radiotherapy. Secondary Objective(s): To evaluate the effect of both neoadjuvant regimens on clinical and pathological response rate (in particular relief of dysphagia, improvement in health related quality of life (HRQL), endoscopic regression, and CT-PET evidence of tumour response), tumour regression grade, node-positivity, post-operative pathology, disease-free survival, time to treatment failure, toxicity, post-operative complications and HRQL. Exploratory Objective(s): Translational Research: The collection of blood and tissue samples for storage in the bio bank for future research. Methods: This is a multicentre phase III open-labelled, randomised controlled trial. Eligible patients will be randomised in a 1:1 fashion between the MAGIC regimen (ECF/ECX chemotherapy) or the multimodality therapy (CROSS protocol). The trial design will apply comprehensive pre-treatment staging, strict surgical, pathological and radiological standards and a modernised design and delivery of radiation therapy. How the results of this research will be used: Results from this study will provide definitive evidence on the use of neoadjuvant chemo radiotherapy in patients with oesophageal cancer following resection and therefore will directly influence clinical practice in the UK. Trial findings will provide important information on the pattern of in-hospital postoperative complications and quality of life in this patient population. A bio-bank of tissue and blood samples will provide a unique repository for future translational research, facilitating the identification of biomarkers that will predict patient response to treatment and guide the design of clinical studies in the future.


Research activity codes: 6.1 PHARMACEUTICALS;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Combination Therapies Targeting Immune Evasion In Pancreatic Cancer
Funder: Cancer Research UK

Abstract: Background Pancreatic ductal adenocarcinoma (PDAC) has one of the worst outcomes of any cancer, with a clear need to develop novel therapeutic approaches. Immunotherapeutic strategies are showing efficacy in several other cancer types, but progress in PDAC has been slow with poor efficacy of single agent regimens. However, our work, and the work of others is showing that understanding active immune avoidance mechanisms, and targeting these using combination therapies can lead to meaningful responses. Emerging data suggests that chemotherapy significantly alters the immune system and the tumour microenvironment (TME), with responses potentially determined by the type of prior treatment. This is important, as therapeutic development of immune agents is mostly focused in 2nd-line or later, after initial chemotherapy in many cancer types, particularly pancreatic cancer. Whilst these data suggest that pre-treatment may profoundly impact immunotherapeutic approaches, we have little understanding of the molecular pathology of “post-chemotherapy” tumours, in any cancer, let alone PDAC. As a consequence, the overall aim of this proposal is to define immune processes in PDAC after 1st-line chemotherapy, and to pre-clinically assess therapeutic combination strategies that emerge from these analyses to build platforms of evidence to advance them to clinical testing. Aims 1) Define immune avoidance mechanisms active in the tumour and its microenvironment after 1st-line therapy in Genetically Engineered Mouse Models (GEMMs) of PDAC. 2) Define immune avoidance mechanisms after 1st-line therapy in patients, including participants in clinical trials. 3) Assess hypothesised combination therapies targeting immune mechanisms defined by the integrated analysis of data from Aims 1 and 2 in GEMMs. Methods The molecular pathology of post-chemotherapy PDAC will be defined using RNAseq, protein expression and genomic readouts in preclinical models and in human samples from patients treated in our centres and from participants in clinical trials. Analyses of these data will generate hypothesised novel combination therapeutic strategies targeting immune evasion in PDAC that will be tested in immune-competent GEMM systems with the goal of building a robust preclinical platform of evidence to take specific approaches into clinical testing. How the results of this research will be used Preclinical platforms of evidence that support clinical testing of specific combinations will be taken into Precision-Panc clinical trials. We previously demonstrated success of this approach with a combination therapy we developed (CXCR2 + PD-L1 inhibition; Steele et al. Cancer Cell 2016), which is currently in clinical testing.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/13/005: InPACT - International Penile Advanced Cancer Trial (International Rare Cancers Initiative study - IRCI 004) (supported by Stand Up To Cancer)
Funder: Cancer Research UK

Abstract: BACKGROUND Penis cancer is rare with a limited body of evidence on which to base the majority of management decisions. There were 519 new cases in the UK in 2009, and 92 deaths. Locoregional lymph node status is the most clinically significant prognostic factor. Conventional management for patients with involved groin nodes is therapeutic inguinal lymph node dissection (ILND). Adjuvant chemoradiotherapy is frequently used following groin dissection where disease has infiltrated through the wall of the lymph node ("extra-capusular extension"), but experience from other cancers has led to increasing interest in its use in the neoadjuvant setting. Patients with a high burden of inguinal nodes and those with extra-capsular extension are often offered prophylactic pelvic lymph node dissection (PLND), although it is unclear whether this improves survival AIMS The aim is to answer two key questions in the management of patients with locally advanced squamous carcinoma of the penis: 1. Is there a role for neoadjuvant therapy and if so is chemotherapy or chemoradiotherapy better? 2. What is the role of prophylactic PLND following ILND in patients at high risk of recurrence? METHODS InPACT is a multiple-randomisation phase III trial (part of the International Rare Cancers Initiative) with a Bayesian design. Stage 1 stratifies patients into disease burden groups based on radiological criteria, and on these criteria allows randomisation in up to three initial treatment arms: A) standard surgery (ILND); B) neoadjuvant chemotherapy; or C) neoadjuvant chemoradiotherapy. All patients receive ILND. Stage two then stratifies patients into risk groups based on pathological criteria with patients at high risk of relapse being randomised to either: P) no PLND; or Q) PLND. Patients who have received neoadjuvant chemoradiotherapy are randomised to PLND or surveillance. Patients who received neoadjuvant chemotherapy or upfront surgery are randomised to PLND followed by adjuvant chemoradiotherapy or adjuvant chemoradiotherapy alone. The aim is to identify all eligible patients through specialist networks prior to ILND, however entry to the trial at stage 2 is permitted. The target sample size is 400 patients internationally recruited over 5 years. The primary endpoint is overall survival; key secondary endpoints include feasiblity of randomisation in stage 1; response rates after neoadjuvant therapy and time to loco-regional recurrence. UTILIZATION OF RESULTS The study will support clinical decision making and define best practice based on current standard modalities (surgery, chemotherapy, radiotherapy). It will, then, provide a basis for all future trials in this disease.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS