NIHRDataInsights/HRCSData huggingface dataset:
Title: Targeting the secretory apparatus in multiple myeloma
Funder: Cancer Research UK

Abstract: BACKGROUND Multiple myeloma (MM) is a tumour of transformed plasma cells and one of the commonest haematological malignancies. Approximately 4.000 people in the UK are affected by MM every year, and it remains a debilitating and incurable disease. MM cells are dependent on specialised mechanisms that regulate intracellular protein metabolism to accommodate the secretion of large amounts of immunoglobulins. One of these mechanisms is the degradation of misfolded proteins. These proteins accumulate in the endoplasmic reticulum (ER) of cells with high secretory demand and can cause toxic ER stress. Misfolded proteins are exported from the ER to the cytosol for degradation by the proteasome through a process known as ER-associated protein degradation (ERAD). The toxicity of proteasome inhibitors for MM cells is thought to be mediated partly through ERAD impairment. However, the clinical effectiveness of proteasome inhibition is limited, possibly due to incomplete ERAD disruption. AIMS In this project, I will investigate how novel approaches of targeting ERAD could be used for therapeutic purposes in MM. The main aims will be to study the cellular effects of inhibiting p97 (p97-i), a protein dislocase with various cellular functions that has a central role in ERAD by extracting misfolded proteins from the ER and delivering them to the proteasome. I will study the types of secretory stress responses that are triggered by p97-i in different cells, and determine how they differ from proteasome inhibition. I will also test whether the kind of secretory load determines cellular p97-dependence. Furthermore, I will analyse the wider impact of p97-i on the cellular proteome. And, based on my findings that dual inhibition of p97 and the proteasome is highly toxic to MM cells, but not to fibroblasts, I will investigate whether targeting a combination of ERAD pathways is a feasible therapeutic approach. METHODS The investigations will be performed in a variety of cell lines and primary cells. p97 will be targeted with small molecule inhibitors and genetic loss-of-function experiments; classical cell biology approaches will be combined with the analysis of the ultra-structure of secretory organelles, and new proteomic strategies. HOW THE RESULTS WILL BE USED The project builds on preliminary data suggesting that p97 is a viable target for therapeutic intervention and worthy of further exploration. It will deliver important new biological insights into fundamental mechanisms of ERAD impairment in multiple myeloma and other cancers that have the potential for translation into clinical practice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Next-generation sequencing to identify genes that predispose to colorectal cancer
Funder: Cancer Research UK

Abstract: Background and Aims Although some of the genetic causes of colorectal cancer are known, there exists a large and important group of patients whose disease has a priori a strong genetic basis, but for whom the causes are unknown. The aim of my project is to identify and characterise genes that predispose to colorectal cancer, with a particular focus on patients who develop multiple colorectal tumours but who do not carry mutations in the known predisposition genes. Methods The project will involve the collation of patient samples and clinico-pathological data, the analysis of next-generation sequencing data from these patients, and replication of selected findings from the sequencing in a larger cohort of patients with colorectal adenomas and carcinomas. If time allows, I shall also perform a limited number of functional assays on genetic variants that I have found. How the data will be used My results will contribute to the clinical management of patients with colorectal tumours in terms of classification, risk prediction and preventive screening of both probands and family members. During this project, I shall receive training in molecular genetics and in selected other fields, such as data analysis, statistics and bioinformatics. I shall use the data generated and the experience gained to prepare an application for a Clinical Research Fellowship to study for a PhD degree.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/08/003: A DNA and bone marrow sample bank from patients with essential thrombocythaemia enrolled in the PT1 Trial.
Funder: Cancer Research UK

Abstract: Background: The high-risk and intermediate-risk arms of the PT-1 trial are the two largest randomised studies in ET and, together with the low-risk arm, form an important cohort of patients with long-term prospective follow-up data and centralised review of clinical end-points. Results from this suite of trials have resulted in numerous important publications to date (New England Journal of Medicine, The Lancet, Blood and Journal of Clinical Oncology). Aims: To use the PT-1 trial samples to create: • A peripheral blood and bone marrow sample bank. • A bone marrow trephine archive. • A sample bank from patients undergoing leukaemic or myelofibrotic transformation. Methods: We propose to: • Collect peripheral blood, serum and bone marrow trephines from patients newly enrolled on the trial, and from those undergoing leukaemic or myelofibrotic transformation. • Obtain follow up samples from patients already enrolled in the trials by requesting blood and buccal swabs from those still alive, and extracting DNA from bone marrow slides of those who have died. • Use whole genome amplification to expand DNA samples. How the results of this research will be used: Samples from this sample bank have already resulted in multiple publications in recent years. In order to build on this established bank of knowledge, we have begun to generate paired tumour and constitutional DNA samples for whole exome or whole genome sequencing in collaboration with the Sanger Institute. This mutation discovery programme enables a more detailed description of each patient and will be combined with clinical parameters to determine whether mutation signatures are associated with diagnosis, response to therapy, risk of progression to accelerated phase disease, or transformation to acute leukaemia.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Sample collection, sample processing and central pathology review with slide scanning from patients entering the UK NCRI ST03 clinical trial
Funder: Cancer Research UK

Abstract: Background The MRC ST02 (MAGIC) trial demonstrated that peri-operative chemotherapy with epirubicin, cisplatin and 5–fluorouracil (ECF) significantly improved survival compared to surgery alone in patients with gastric adenocarcinoma. Despite this improvement, the 5 year survival rate of patients with gastric cancer is only 36% at best. The ST03 trial investigates whether the addition of Bevacizumab (Bvac), a monoclonal antibody against vascular endothelial growth factor (VEGF), to peri-operative ECCap (Cap=capecitabine, oral form of 5FU) combined with post-operative Bvac maintenance therapy improves patient's outcome compared to peri-operative ECCap alone ('ST02-type' treatment). It is anticipated that not all patients will benefit from the addition of Bvac in the ST03 trial, but there is currently no evidence-based marker available to aid pre-treatment patient selection. The trial will recruit approximately 1000 patients with oesophago-gastric adenocarcinoma. Closure of the trial is anticipated for 2013/2014. Aims This project aims to collect and process a pre-treatment blood sample, the pre-treatment biopsy paraffin block, and blocks with tumour and normal from the resection specimen. Furthermore, selected routine histology slides will be scanned and made available for future image analyses and a central pathology review of all cases will be performed to ensure high quality pathology data for the trial analysis. Methods DNA will be extracted from the white blood cells of the collected blood samples as well as from the paraffin embedded material. Tissue microarrays will be constructed from tumour and normal tissues. Histological slides from the biopsy and the resection specimen will be scanned and a central pathology review will be performed by expert histopathologists. How the results of this research will be used This grant will not produce any research results as such but will result in a material collection to be used for future research. The results from the central pathology review are essential for the analysis of the clinical trial results.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/019: ReBeL study: a randomized phase I/II trial of lenalidomide and rituximab with or without bendamustine in patients 18 years or older with relapsed follicular lymphoma. A HOVON/GLSG study.
Funder: Cancer Research UK

Abstract: Background: Follicular lymphoma (FL) is a common and incurable subtype of lymphoma. Most patients suffer multiple inevitable relapses of disease eventually leading to their demise. There are no standard treatments for relapsed FL and currently no open/planned clinical trials in the NCRN portfolio for this indication. The Hovon/GLSG phase l/ll ReBeL trial in relapsed FL has recently opened phase l in The Netherlands and Germany. UK participation in phase ll has been invited and endorsed by the NCRN low grade subgroup. ReBeL is investigating Lenalidomide, rituximab and bendamustine, drugs with promising individual activity in FL in first line and in relapse. Since the toxicity of these drugs is limited and in part non-overlapping, they are good candidates for combination therapy. <br/><br/>Aims: The main study endpoints of phase I (The Netherlands and Germany only) are the dose limiting toxicity (DLT) and recommended dose level (RDL) of combined lenalidomide, bendamustine and rituximab for use in phase II. The main study endpoints of phase II (all Sites) are efficacy (CR rate) and toxicity of the two study arms (arm A: lenalidomide and rituximab, arm B: lenalidomide, rituximab and bendamustine).<br/><br/>Methods: Patients aged 18 years or older with relapsed CD20+ FL and a maximum of 3 prior regimens will be eligible. The phase II trial is multicentre, prospective and randomised with two experimental arms All patients will receive 6 induction cycles administered over 6 months followed by maintenance Rituximab three monthly for 2 years. In the phase II induction cycles, lenalidomide and rituximab with/without bendamustine will be given at the RDL determined in phase l (lenalidomide 10/15/20 mg on day 3-21 of a 28-day schedule, bendamustine 70/90 mg/m2 on day 1,2 and rituximab 375 mg/m2 on day 1). The expected duration of accrual is 3 years and patients will be followed for 8 years after registration. Phase ll will enrol 150 patients in total (~60-80 from the UK over 2 years, starting September 2012). Several safety analyses are planned during phase I and one interim analysis in phase II. <br/><br/>How the results will be used: The hypothesis is that both treatment arms will be effective with acceptable toxicity. Results will inform the design of future pivotal randomised phase lll trials: the chemotherapy-free lenalidomide and rituximab combination is potentially attractive in older/frailer/heavily pre-treated patients where further chemotherapy is undesirable, whilst the three-drug combination is promising as an effective combination that could potentially improve survival.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Pharmacogenetic markers of irinotecan toxicity and outcomes in metastatic colorectal cancer.
Funder: Cancer Research UK

Abstract: Background: Polymorphism of genes involved in drug handling is an important potential source of inter-patient variability in toxicity and efficacy. However pharmacogenetic relationships for anticancer drugs are poorly characterised and inadequately validated, so are rarely clinically applicable. Irinotecan is commonly used for patients with advanced colorectal cancer (aCRC) but causes significant toxicity. UDP-glucuronosyltransferases have a well described role in irinotecan clearance. In 2005 the FDA approved a genetic test for UGT1A1*28 and altered the package insert to include toxicity and dosing warnings relating to this allele. This was based upon the results of two studies using different regimens, with a total of only 132 patients, with thirteen UGT1A1*28 homozygous patients of whom 8 experienced toxicity. Subsequent attempts to qualify this relationship, including data from 208 patients in the UK FOCUS trial, do not support the use of UGT1A1*28 as a single biomarker. Several other common polymorphisms affect the irinotecan metabolism and clearance pathway, making it unlikely that clinical risk would be adequately determined by a single marker. Aims: We will validate or refute the significance of UGT1A1*28 homozygosity (biomarker qualification); we will also assess the additional contribution of data from several further genetic variations in the UGT1A1 sequence, in other UGT1A isoforms and in related genes involved in irinotecan metabolism and transport. Methods: Blood samples from 350 aCRC patients who received single agent irinotecan in the PICCOLO trial will be analysed. Genotype information will be correlated with toxicity (incidence of grade 3-4 diarrhoea and neutropenia within 12 weeks of starting treatment) and outcomes. Beyond UGT1A1*28, candidate polymorphisms have been selected based upon their known role in irinotecan metabolism and elimination, and/or evidence from previous literature. Genotyping will be performed using pyrosequencing. With the expected genotype frequencies, we will have 80% power to detect a minimum relative risk of 2.3 or more for UGT1A1*28 homozygosity assuming a recessive model of inheritance (P=0.05). Indicative power calculation have been made for haplotype and combined models. How this research shall be used: By comprehensively examining biologically plausible polymorphisms this research could guide the development of a clinically applicable pharmacogenetic test to predict irinotecan tolerability. Ultimately, this would contribute to the individualisation of treatment for aCRC patients by drug avoidance, dose-adaptation or dose-escalation according to risk.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Trans-PERSEPHONE and Trans-PERSEPHONE-SNPs: the pharmacogenomics and pharmacogenetics of adjuvant trastuzumab.
Funder: Cancer Research UK

Abstract: The hypothesis being tested in Trans-PERSEPHONE and Trans-Persephone-SNPs is that there are germline (pharmacogenetics) and somatic (pharmacogenomics) determinants of outcome (only 50% of patients destined to relapse gain benefit) and toxicity (up to 4% will develop significant clinical heart failure) with adjuvant trastuzumab therapy. The aim of Trans-PERSEPHONE and Trans-PERSEPHONE-SNPs is the identification of high/low risk sub-groups by using both candidate gene and empirical approaches. The identification of these pharmacogenetics/pharmacogenomics determinants will require large uniform cohorts such as in the PERSEPHONE clinical trial and will in future lead to the prospective characterization of patient sub-groups with increased/decreased benefit, resistance and toxicity.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Tumour Cell Migration
Funder: Cancer Research UK

Abstract: This group studies the control of actin dynamics at the leading edge of migrating cells. The group specifically utilises state of the art fluorescence-based microscopic imaging to visualise assembly and disassembly of leading edge actin structures at the protruding plasma membrane. This is important as cancer cells often display aberrant motile behaviour as a consequence of de-regulated actin dynamics


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Experimental Cancer Medicine Centre (ECMC): ICR
Funder: Cancer Research UK

Abstract: Background: Optimal early clinical anticancer drug development is an increasingly complex, biomarker-driven process. Relevance to cancer: The optimized and accelerated development of novel molecularly targeted anticancer drugs is vital to improving the outcome of patients suffering from cancer. Specific Aims of the Centre: The specific aim of our ECMC will be the conduct of early clinical trials in advanced cancer patients. We plan to conduct hypothesis-testing, biomarker-driven trials focused on evaluating drug tolerability, determining dose-limiting toxicity and maximum tolerated dose and questioning and answering key biological hypotheses about human cancer. We will pursue the ‘Pharmacological Audit Trail’ utilizing pharmacokinetic-pharmacodynamic studies, intermediate endpoints and putative predictive (patient enrichment) biomarkers to molecularly stratify patients and expedite the translation of cancer research in early clinical trials. Implications: Such trials can accelerate drug development, maximize drug development and provide critically important information on disease biology supporting reverse translation, further laboratory research and new target identification. Disease Focus Areas: Breast, Colorectal, Kidney, Lung, Melanoma, Ovarian, Pancreatic, Prostate, Sarcoma .


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

Abstract: Background: The Newcastle ECMC brings together translational scientists and clinical researchers to carry out early phase trials of potential new cancer drugs, building on an established reputation in drug discovery and development and underpinning expansion in these areas and also in cancer imaging research and biobanking. Relevance to cancer: The ECMC allows the generation of translational research data derived from adult oncology trials, surgical oncology trials (particularly prostate cancer) and paediatric oncology trials to direct drug development and target discovery activities. Involvement of surgical oncology and pathology allows the generation of tissue banks to facilitate the development of molecular biomarkers and improve treatment outcomes. Specific aims of the centre: The Centre aims to increase access to anti-cancer novel agents for adults and children in the North East, to use clinical pharmacology to optimise drug delivery and safety in adults and children, to develop biomarkers in tissue or using imaging techniques to improve outcomes with new treatments and to build a tumour tissue banking resource for further target discovery research and future drug development. Disease focus areas: Breast, Ovarian, Prostate, All Sites.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Experimental Cancer Medicine Centre (ECMC): Leicester Centre for developing chemopreventive agents, targeted therapies and biomarkers to personalise cancer management
Funder: Cancer Research UK

Abstract: Background Leicester ECMC has expertise in development of new strategies to reduce cancer incidence, identification of biomarkers, and discovery of new therapies. Activities are organised in four themes: Chemoprevention, Biomarker development for personalised medicine, Strategies to optimise drug selection and identification of New drugs for development. Relevance to Cancer Effective chemoprevention agents would reduce cancer incidence and biomarkers could detect cancer at an early, more curable stage. Identifying new drugs and targeting them to specific patients will increase the chance of benefit, reduce unnecessary toxicity and cost, and improve outcomes. Aims of Centre Cancer stem cell models will be used to help select chemopreventive agents for clinical development. Clinical trials will include evaluation of diindolylmethane to prevent invasive bladder cancer and a biomarker-driven colorectal adenoma prevention study. Biomarker development will involve use of plasma nucleic acids for detection and monitoring of breast/lung cancers whilst a novel ex-vivo tumour explant culture system will be employed to predict drug efficacy against NSCLC. Effects of targeted agents and optimal dosages will be evaluated in pre-operative „Window Studies?. Phase I/II trials include development of BCL6 antagonists, identification of NIMA-related kinase inhibitors and assessment of eicosapentaenoic acid and curcumin for pancreas and colon cancers respectively. Disease Focus Areas: Basic Research, Bladder, Breast, Colorectal, Leukaemia, Lung, Pancreatic.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);3.5 RESOURCES AND INFRASTRUCTURE (PREVENTION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Experimental Cancer Medicine Centre (ECMC): UCL
Funder: Cancer Research UK

Abstract: UCL ECMC is committed to performing world-class clinical cancer research to discover and develop new treatments and improve the outcome for patients. Our centre is fully integrated within the University and NHS providing a seamless link between fundamental scientific discoveries and their clinical application. Specific aims include 1. To increase the number of early phase clinical trials and conduct them efficiently and safely within an environment that is quality controlled and patient focussed. In parallel we will expand our in-house drug discovery program, collaborating with experts within and outside UCL to develop new treatments for cancer. 2. To develop novel methods of delivering and enhancing the outcome from radiotherapy by the use of targeted therapy and rational combinations with systemic therapies. 3. To build on our expertise in cellular and gene therapy to improve the outcome for patients with haematological malignancy. 4. To exploit platform technologies in genomics, epigenetics and circulating biomarkers to identify novel targets and stratify patients for therapy in order to maximise efficacy and minimise toxicity. We will contribute expertise, data and education, and engage both patients and the public to deliver the strategic aims of the wider ECMC Network. Disease focus areas: Bone, Brain, Colorectal, Hodgkin's Disease, Leukaemia, Liver, Lung, Non-Hodgkin's Lymphoma, Ovarian, Pancreatic, Sarcoma, Relevant to all Types of Cancer.


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