NIHRDataInsights/HRCSData huggingface dataset:
Title: The validation of interim outcome measures for the evaluation of interventions promoting increased cancer awareness and early detection
Funder: Cancer Research UK

Abstract: Background: Improvement in UK cancer survival rates could be achieved by improving cancer awareness, early detection and referral, and patient management. Cancer screening evaluation has demonstrated the benefit of using standardised outcome measures which minimize potential bias in results and of modelling the impact of screening on outcomes, taking into account the advantages and disadvantages of screening. Early detection initiatives would benefit from a similar approach to ensure the development of effective initiatives. Validated measures are required for short-term and interim outcome measures. Longer-term outcomes may be predicted from these to overcome the difficulties including the large sample sizes and time required to collect long-term data. Aims: 1. to review data available on interim outcome measures used to evaluate awareness and early detection initiatives for colorectal and ovarian cancers, to study the relationship between short-term and interim outcome measures, and to predict long-term outcomes measures 2. to report the use of interim outcome measure to study the effectiveness of initiatives with specific reference to social inequalities 3. to make recommendations for validated outcome measures applicable to all cancers likely to benefit from early detection Methods A systematic review will be conducted to report results on outcome measures for colorectal and ovarian cancers: • Consultation rates for symptoms, diagnostic testing and referral • Cancer incidence, mortality and survival • PPVs of symptom scores, and performance of diagnostic procedures • the relation between outcome measures, and social deprivation and ethnicity. The measures will be assessed using standardised criteria including data quality, biases and reliability of predicted outcomes. One key measure will be cancer incidence by stage. An increase in the percentage of cancers presenting at an early stage has been used as an outcome measure for awareness interventions but this will not always translate into a reduction in late stage disease or mortality. Decision analysis will be used to model ways in which this outcome might be reflected in subsequent rates of late stage disease. Other measures associated with primary care include the positive predictive value (PPV) of symptom scores, diagnostic test performance, PPV of referral and workload associated referral, in particular false positives. The relationship between short-term and interim measures, and prediction of their relation to the longer-term outcomes of cumulative incidence rate of late stage cancer and cancer mortality will be studied using decision analysis. Results will be reported to policy makers, and committees overseeing new cancer awareness initiatives.


Research activity codes: 4.3 INFLUENCES AND IMPACT;8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES)
Health categories: CANCER AND NEOPLASMS
Title: The genetic and epigenetic effects of folic acid deficiency in a murine model
Funder: Cancer Research UK

Abstract: Background. The results of recent human and animal studies have provided strong evidence for the epigenetic effects of a dietary deficiency of methyl donors on cancer risk and some other common diseases. However, the mechanisms underlying the links between epigenetic alterations and disease remain elusive. Given that the development of cancer is a multistep process of mutation accumulation, it is plausible that the reported long-term changes in the pattern of DNA methylation following dietary restriction may destabilise the genome. Relevance to cancer. The proposed research aims to establish the long-term epigenetic effects of a folate-deficient diet on genome stability, patterns of DNA methylation and gene expression in treated mice and their offspring, and could elucidate the unknown mechanisms underlying such changes. An in depth analysis of the mechanisms underlying the links between environmentally-induced epigenetic changes and disease could substantially improve the identification of the determinants of cancer. A better understanding of the pattern of transmission of epigenetic changes should provide experimentally based estimates of the delayed epigenetic effects of exposure to a broad range of environmental factors, of direct relevance to cancer research. This work could ultimately improve early diagnostic testing for aberrant DNA methylation that can lead to cancer. Aims: (i) to establish whether a folate-deficient diet results in long-term changes in mutation rate in treated mice and their offspring; (ii) to establish whether a folate-deficient diet can alter the pattern of DNA methylation in treated mice and their offspring; (iii) to establish whether a folate-deficient diet affects gene expression in treated mice and their offspring. Plan of research. Male mice will be maintained for 12 weeks on a folate-deficient diet. To establish the effects of diet on mutation induction and transgenerational instability, the frequency of mutation at an expanded simple tandem repeat (ESTR) locus will be determined in the treated mice 0-12 weeks after dietary exposure and in their offspring. Using the MeDIP assay, the methylation status of mouse gene promoters will be established. To investigate whether epigenetic methylation changes are heritable, the patterns of DNA methylation will also be assessed in the offspring of treated mice. Using microarrays, the expression profiles of the same control and treated animals will also be analysed, addressing the following questions: (i) do diet-related alterations in the epigenetic landscape affect the expression profiles of methyl-deficient animals? (ii) do paternal dietary deficiencies affect gene expression in their offspring?


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS
Title: Grant support for CRUKD/13/001 Phase IB & Phase II trials to determine the immunogenicity & tolerability of extended schedule vaccination with MVA-EBV vaccine in patients with EBV+ nasopharyngeal carcinoma
Funder: Cancer Research UK

Abstract: Nasopharyngeal carcinoma (NPC) occurs worldwide including in the UK but is particularly prevalent throughout S.E.Asia. NPC consistently harbours Epstein-Barr virus (EBV) which expresses two viral proteins, EBNA1 and LMP2. In previous work we have identified these antigens as targets of CD4+ and CD8+ T cell responses. Our objective is to complement current NPC therapy by vaccination with a recombinant modified vaccinia Ankara (MVA) virus vector that encodes an EBNA1/LMP2 fusion protein in a form that can be processed for both CD4+ and CD8+ T cell recognition. The first in man Phase I trials in NPC patients in remission are complete in the UK and Hong Kong. This grant is providing laboratory support for two further clinical trials with the vaccine. The Phase IB trial in the UK aims to extend the safety data on the vaccine at the highest dose in patients following primary treatment for NPC and investigates in detail the immune effector, memory and recall responses in blood samples taken across vaccine cycles 1-3 and 12 weeks later across a fourth cycle. The Phase II trial in Hong Kong offers 6 vaccine cycles to patients with persistent, recurrent or metastatic NPC with cross-sectional imaging and viral immunity measured at screening and after 3 and 6 cycles. It is designed to determine (i) the clinical benefit rate (responses plus stable disease) as justification to progress to phase III (ii) clinical response rate, progression free and absolute survival (iii) change in circulating EBV genome levels as a biomarker of response (iv) immune responses to EBNA1/LMP2 (v) the effector profile of responding T cells from selected patients by multi-parametric flow cytometry and (vi) extend data on safety and tolerability.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Maintenance of genome stability
Funder: Cancer Research UK

Abstract: Our work focuses on the DNA-damage response (DDR): the set of events that optimises cell survival by detecting DNA damage, signalling its presence and mediating its repair. The importance of the DDR is underscored by defects in it being associated with various pathologies, including neurodegenerative disease, immunodeficiency, premature ageing, infertility and cancer. By working with both yeast and human cells, we are identifying new DDR factors, defining the functions of known DDR components, assessing how the DDR is affected by chromatin structure, and learning how DDR events are regulated. For example, we recently discovered that – like the yeast Sae2 protein – the human CtIP protein functionally interacts with the MRN complex to promote processing (resection) of DNA double-strand breaks (DSBs) to generate single-stranded DNA that activates the DDR kinase ATR and triggers DNA repair by homologous recombination. Moreover, we found that CtIP and Sae2 share a highly conserved cyclin-dependent kinase (CDK) phosphorylation site, and discovered that its phosphorylation facilitates resection, thus promoting ATR signalling and HR in S/G2 but not G0/G1. Furthermore, we recently discovered that the yeast Sgs1 helicase and its human counterpart BLM (mutated in cancer-predisposed Bloom syndrome patients) promote resection, HR and ATR signalling by a pathway that is distinct from that mediated by MRN and Exonuclease I. Another highlight over the past year has been our demonstration that phosphorylation-dependent interactions between MRN and the DDR-mediator protein MDC1 are required for the association of MRN with chromatin flanking DSB sites. Our current work is geared towards further defining the mechanisms and biological functions of these and other DDR events.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Binding properties governing T cell receptor recognition of tumour antigens
Funder: Cancer Research UK

Abstract: BACKGROUND AND RELEVANCE TO CANCER: There is growing interest in the therapeutic potential of adoptive immunotherapy with T cells that have been modified to express T cell receptors (TCRs) specific for tumour antigens. These TCRs recognize peptide fragments of tumor-specific proteins (p) presented on Major Histocompatibility Complex proteins (pMHC) on the surface of tumor cells. One factor hampering these efforts is that it remains unclear what the optimal TCR/pMHC binding properties are for effective antigen recognition. Indeed it is not even clear which binding properties should be measured. Until recently binding was measured using soluble forms of the molecules in solution or three dimensions (3D). In reality TCR and pMHC are cell-surface molecules restricted to the two dimensional (2D) plane of the membrane, and their interaction is subjected to mechanical stress. Recent work from our laboratory on a tumor antigen model system suggested that both the dissociation (koff) and association rate constants (kon) measured in solution appear to be important predictors of the T cell response. However, the dynamic range of binding properties was relatively small and the predictive power of 3D binding properties was modest. AIMS: - To use high affinity TCRs and pMHC variants to determine the optimum binding properties governing T cell activation, motivated by predictions from mathematical modeling. - To measure membrane (2D) and mechanical binding properties of TCR/pMHC interactions and determine how they relate to solution (3D) binding properties and pMHC potency. - To use this information to build mechanistic molecular models of TCR recognition and thereby formulate rules for improving T cell adoptive immunotherapy. PLAN OF INVESTIGATION: Our approach will be to measure 3D, 2D and mechanical binding properties of high affinity variant(s) of the NYESO-specific TCR 1G4 for panel of tumour pMHC variants and to correlate these with functional tumour antigen recognition. 3D and 2D binding properties will be measured by surface plasmon resonance and glass-supported planar bilayers, both of which are established in our laboratory. Mechanical properties will be measured in collaboration with Professor Pierre Bongrand using a laminar flow methods established in his laboratory. Mathematical modeling and data analysis will be performed in our laboratory.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Histone acetylation and DNA repair factor recruitment for Global Genome Nucleotide Excision Repair throughout the yeast genome
Funder: Cancer Research UK

Abstract: We use S.cerevisiae as a model to study Nucleotide Excision Repair that removes DNA damage. NER is highly conserved and many of this yeast’s genes are homologous to those in Humans. We focus on the Global Genome sub-pathway repairing repressed genes/non-transcribed regions and use UV radiation to damage DNA. Cellular DNA is packaged as chromatin and GG-NER requires it to be modifying to operate efficiently. We examined repair of a few genes and histone H3 and H4 acetylation facilitate GG-NER, but the extents of these acetylations vary for different genes. Some H3 acetylation requires the histone acetyltransferase (HAT) Gcn5 whose recruitment depends on the GG-NER protein Rad16. However, many histone acetlyations occur in the absence of Gcn5. We do not know the relationships between GG-NER and histone acetylations genome-wide. Unrepaired DNA damage creates genetic instability and cancer is one consequence. DNA repair reduces the burden and defects in it are associated with cancer-prone disease. The GG-NER pathway is defective in humans suffering with the cancer-prone disease xeroderma pigmentosum and belonging to complementation group C. This defect in a core GG-NER protein gives an extreme phenotype; a 2000-fold increase in UV-induced skin cancer. Our research suggests that there are HATs that influence GG-NER in selected regions of a genome. We hypothesise that specific regions of the yeast genome require different H3 and H4 acetylations to afford efficient GG-NER. For the entire genome, we will determine the roles of H3 and H4 acetylation in GG-NER, whether all of these events require Rad16, and if they govern the recruitment of a damage recognition factor. The information will help understand the factors that govern GG-NER operating on chromatin and assist researchers in the identification of human genes regulating GG-NER in specific genomic locations. For this proposal we developed a ChIP-Chip microarray method to quantify UV damage throughout the genome. We employ a UV damage-specific antibody (to Cyclobutane Pyrimidine Dimers) to selectively immunoprecipitate genomic regions containing CPDs, These are identified following PCR and quantified on microarrays versus the total genomic DNA using dual dye labelling. The method is quantitative and the quality control metrics are in place. We will examine throughout the genome GG-NER, histone acetylation and the recruitment of a NER-specific damage recognition factor (the latter two events via conventional ChIP- Chip) in repair competent cells, in a range of HAT mutants, and determine the role of Rad16 in these events.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: In vivo manipulation of Fc gamma Receptor expression and activity through macrophage polarization
Funder: Cancer Research UK

Abstract: Monoclonal antibodies (mAb) have become established in the treatment of a variety of malignancies and autoimmune disorders - transforming patient outcomes. Despite this undoubted impact, responses remain variable with the mechanisms of action and tumour resistance controversial. Several strategies are being employed in an attempt to improve responses and one area where there is growing interest is re-programming the tumour microenvironment to augment effector cell recruitment and function. We and others have shown that antibody immunotherapy relies predominantly on activatory Fc gamma Receptor (FcgammaR) expressing macrophages for effector function. However, tumour associated macrophages (TAM) can have a pro-tumour phenotype associated with a reduction in the activatory:inhibitory FcgammaR balance which we hypothesise reduces the potency of antibody therapy. How macrophages are manipulated by tumours in vivo and how they may be re-polarised to augment mAb immunotherapy is a critical area of study where data is currently lacking. In this project using a combination of genetically modified mice, in vivo lymphoma models and ex vivo human samples we will: 1) investigate the polarisation status of macrophages in vivo; characterising their phenotype, FcgammaR repertoire and effector capacity in the presence of tumour, 2) assess a panel of clinically relevant TLR agonists for their ability to repolarise macrophages from a TAM-like phenotype to enhance their FcgammaR effector functions and 3) determine the potential of in vivo macrophage FcgammaR repolarisation to augment antibody immunotherapy. Taken together these studies will provide critical information to better understand the role of macrophage FcgammaR polarisation in the tumour microenvironment – particularly in relation to augmenting immunotherapy. Further, it is anticipated that it will identify clinically relevant strategies that may be developed to enhance mAb activity and efficacy in patients.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Identification of novel pathways that suppress sensitivity of cells to PARP inhibition
Funder: Cancer Research UK

Abstract: Cells have evolved a DNA damage response to detect, signal and repair DNA damage in order to maintain genome integrity. Alternate DNA repair pathways exist that combat different varieties of genotoxic stress. In certain instances, however, redundancy between these pathways ensures that should one repair strategy fail, others are available to maintain genome integrity and cell viability. Recently, this phenomenon has been exploited to specifically target cancer cells that are defective in certain DNA repair pathways. For example, BRCA1 and BRCA2 defective breast and ovarian cancer cells are hypersensitive to inhibitors of poly (ADP-ribose) polymerase (PARP) due to their inability to perform homology-directed repair of DNA double strand breaks generated as replication forks encounter single strand breaks during S-phase. Given the therapeutic potential of PARP inhibitors, identifying pathways that exhibit a synthetic lethal relationship with these agents is of interest. In addition to providing insights into fundamental aspects of DNA repair, these studies have the potential of identifying novel therapeutic targets that when disrupted will increase efficacy of currently available cancer treatment regimes. Relatively simple genetic model organisms provide a valuable tool to perform these experiments. However, this approach is limited by the lack of certain human DNA repair proteins in commonly used model organisms For example, PARPs are absent in the genomes of S. cerevisiae and S. pombe. Recently, we initiated a study of DNA repair in Dictyostelium and found that certain human DNA repair proteins absent in yeast, worms and flies are conserved in this organism. In this regard, similar to humans, Dictyostelium contains multiple PARPs and our data illustrate these are targets for currently available PARP inhibitors. The aims of this research are to exploit Dictyostelium to identify novel pathways that when disrupted in combination with PARPs result in cell death or sensitivity to genotoxic stress. This will be achieved by two complementary strategies. We will asses the synthetic lethal relationship of different PARP isoforms with currently identified DNA repair pathways. In parallel, we will perform genetic screens in Dictyostelium to identify novel DNA repair and other pathway components that suppress sensitivity of cells to PARP inhibitors. Results obtained from these experiments will be extended to identify novel mechanisms that suppress sensitivity of human cells to PARP inhibitors.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/10/050: EORTC 30073: Randomised Phase III trial comparing immediate versus deferred nephrectomy in patients with synchronous metastatic renal cell carcinoma
Funder: Cancer Research UK

Abstract: 1) Renal cell cancer (RCC) is the 7th most frequent cancer and accounts for 2-3 %_x000D_ of all new cancer cases worldwide. Currently, sunitinib is the only approved first-line_x000D_ treatment for patients with metastatic RCC (Mr.CC) which can be used right up to or_x000D_ soon after surgery. The sunitinib related improvements in the treatment of Mr.CC_x000D_ and the observed responses seen in primary tumors challenges the need for_x000D_ nephrectomy and its benefit in the metastatic setting. However there is some_x000D_ evidence to support that a subgroup of Mr.CC patients benefit from nephrectomy in_x000D_ combination with sunitinib which has led to a rationale for changing the sequence of_x000D_ nephrectomy and sunitinib to deferred nephrectomy and investigation of pretreated_x000D_ primary tumor tissue in vitro. In addition, several potential clinical benefits can be_x000D_ identified for deferred nephrectomy following targeted therapy that may improve the_x000D_ clinical and surgical outcome._x000D_ 2) To investigate whether deferring nephrectomy in patients who receive sunitinib_x000D_ has an effect on disease control by optimizing the sequence of surgery for Mr.CC._x000D_ 3) A randomised multinational multicentre phase III trial with a primary endpoint of_x000D_ progression-free survival._x000D_ 4) This trial is an international intergroup trial has the potential to influence practise_x000D_ worldwide.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.4 SURGERY
Health categories: CANCER AND NEOPLASMS
Title: CRUK/07/013: COUGAR-02: A randomised phase III study of docetaxel vs active symptom control in patients with relapsed oesophagogastric adenocarcinoma
Funder: Cancer Research UK

Abstract: Background Most patients with a good performance status who present with advanced oesophago-gastric cancer receive chemotherapy. Once patients relapse after first-line chemotherapy there is no data to guide further treatment. Although a number of chemotherapy agents are thought to be active in this setting there is no randomised data demonstrating the superiority of chemotherapy over supportive care. Relevance There is an important need to establish whether there is any benefit to chemotherapy in this situation,and to establish a reference regimen for newer regimens to be compared against in future studies. Aims The aim is to assess whether docetaxel chemotherapy is beneficial compared to best supportive care. If docetaxel is shown to be better than supportive care in terms of survival or health-related quality of life then this will become a reference regimen to which other chemotherapy/biological agents can be compared. Outline This is a randomised phase III study. Patients with advanced oesophago-gastric cancer who have relapsed following 1st line chemotherapy will be eligible. Patients will be randomised in a 1:1 ratio(docetaxel: active symptom control). The primary outcome measure of the trial is overall survival. Secondary outcomes are health-related quality of life, response rate and progression-free interval.


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