NIHRDataInsights/HRCSData huggingface dataset:
Title: Identification And Molecular Characterisation Of Metastatic Sporadic Castration Resistant Prostate Cancers (mCRPC) With Homologous Recombination DNA Repair Defects That Can Be Targeted By A Synthetic Lethal Strategy
Funder: Cancer Research UK

Abstract: Background: Metastatic castration resistant prostate cancer (mCRPC) is associated with a high risk of late drug development failure due to inter-patient molecular heterogeneity and poor intermediate endpoint measures of clinical benefit. Platinums have anti-tumour activity in CRPC, but are neither approved nor routinely used; platinum sensitivity correlates with poly(ADP)-ribose polymerase inhibitor (PARPi) sensitivity. Utilising a synthetic lethal strategy, we have shown that the PARPi olaparib has significant anti-tumour activity in BRCA1/2 mutation carrier cancers including advanced mCRPC (Fong PC, et al, N Engl J Med; 2009, Fong PC, et al, JCO, 2010)PTEN loss is common in mCRPC and has been associated with BRCAness and sensitivity to PARP inhibition (Mendes-Pereira AM et al, EMBO Mol Med, 2009). We now hypothesise that PARP inhibitors will have important antitumour activity in sporadic mCRPC. Aims: To conduct a Phase II trial of the PARPi inhibitor olaparib to evaluate its anti-tumour activity in sporadic mCRPC and to_x000D_ clinically qualify a predictive biomarker for PARP inhibitor sensitivity. Methods: We plan to conduct an adaptive, biomarker driven, Phase II clinical trial of olaparib to clinically qualify predictive biomarkers of olaparib sensitivity. We will focus on archival prostate tumour samples to develop putative predictive biomarkers of response to olaparib. We will examine what abnormalities are present in the tumour cells of men who benefit from this therapeutic strategy and how these differ from the men who do not benefit in order to clinically qualify a predictive biomarker of olaparib sensitivity. PTEN immunohistochemistry and FISH will be evaluated; BRCA1 and BRCA2 will only be sequenced in responding patients to minimise cost. Intermediate endpoints of anti-tumour_x000D_ activity will include PSA, RECIST radiological response and circulating tumour cell (CTC) count falls. Exploratory studies will evaluate tumour BRCA promoter methylation; RAD51 foci formation following PARPi exposure in CTC and optional paired tumour biopsies; multi-colour FISH and immunofluorescence studies in CTC. Impact and utility of results: Molecular sub-classification of CRPC into distinct subgroups by predictive biomarkers is critical to decrease the risk of late randomised Phase III trial failure. Identifying a sub-group of advanced nonhereditary prostate cancers that are highly sensitive to PARP inhibitors and developing a biomarker to select these patients will support the conduct of a randomised Phase III trial of olaparib in a selected CRPC_x000D_ patients.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Targeting the unfolded protein response in the production of new treatments for Multiple Myeloma: structural biology support for the design and optimization of IRE1 kinase inhibitors
Funder: Cancer Research UK

Abstract: There is a need to develop new treatments for multiple myeloma, which causes 2,000-3,000 deaths in the UK annually and has a very low 5-year survival rate. Myeloma cells are dependent on the unfolded protein response (UPR), which enables cells to cope with endoplasmic reticulum (ER) stress. X-box binding protein 1 (XBP1) is a crucial component of the UPR that mediates myeloma growth and survival via upregulation of the cytokine IL6 and the adaptive stress response to eliminate misfolded immunoglobulins. The activation of XBP1 requires a splicing event that is catalysed by IRE1, a transmembrane protein resident in the ER. The cytoplasmic domain of IRE1 has both kinase and endoribonuclease (RNase) activities, either of which could be a potential target for the development of inhibitors of XBP1 splicing since the activation of the RNase activity is dependent on autophosphorylation of IRE1. The purpose of this proposal is to provide structural biology support to accelerate the design and optmization of small molecule kinase inhibitors of IRE1. We will determine co-crystal structures of human IRE1 bound to inhibitors to inform the design of more potent compounds. We will develop a system for high-throughput crystallography (HTX) of IRE1 and then work closely with the medicinal chemists in iterative cycles of design, testing and structural biology to improve the inhibitors towards an acceptable lead profile. The research will result in improved IRE1 inhibitors suitable for the study of IRE1 function in multiple myeloma models. In the future, the lead compounds will be developed into a pre-clinical candidate.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: The IMPACT Study: application for a multinational targeted prostate screening study based on genotype
Funder: Cancer Research UK

Abstract: Background_x000D_ Prostate cancer (PrCa) is the commonest solid tumour in men in the West; there are 913,000 cases per year worldwide. There is epidemiological and molecular evidence for genetic predisposition to PrCa. Population based screening is controversial; it has shown a reduction in mortality in two of three reports, however 12 men need treating to save one life. We are therefore aiming to use germline genetic profiling to target PrCa screening to those most likely to benefit because they are at higher risk. Men with BRCA2 germline mutations have been reported to have a relative risk (RR) of PrCa of 5-7, more aggressive disease and a higher mortality rate. Men with BRCA1 germline mutations are reported to have a RR of PrCa of 1.85 under 65 years and may also have a worse prognosis. The role of prostate specific antigen (PSA) screening in these men is being evaluated in IMPACT, a multi-national research study. This is the first prospective targeted screening study in men with a known genetic predisposition to the disease. _x000D_ The reasons for applying at this stage are:_x000D_ (i) pilot data were requested when we originally applied for support for this study and these data have now been obtained and published. _x000D_ (ii) this is a multi-national study and has some prior funding from The Ronald and Rita McAulay Foundation. _x000D_ Aims & Objectives_x000D_ The IMPACT study aims to:_x000D_ 1. Establish a multi-national targeted PrCa screening study in BRCA1/2 mutation carriers and controls _x000D_ 2. Determine whether there are differences between the cohorts in:_x000D_ a) incidence of raised PSA _x000D_ b) incidence of abnormal biopsy _x000D_ c) pathology_x000D_ 3. Determine sensitivity, specificity and positive predictive value of PSA screening and prostate biopsy for PrCa in these cohorts_x000D_ 4. To gain a better understanding of the pathogenesis of PrCa due to a genetic predisposition. _x000D_ Methods_x000D_ Men aged 40-69 years from families with BRCA1 or BRCA2 germline mutations are offered annual PSA screening for 5 years. In addition biological samples are taken for banking for new marker studies. After 5 years of screening all men are offered a prostate biopsy irrespective of PSA level. _x000D_ How the results of this research will be used_x000D_ This work is likely to demonstrate the use of genetics to target screening to identify those at higher prostate cancer risk. It has translational opportunities to move forward the use of genomic medicine in healthcare policy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Signalling by CD244 and Related Receptors in Human Cytotoxic Lymphocytes
Funder: Cancer Research UK

Abstract: Optimising immune cell cytotoxicity is relevant to control of cancer. A lack of understanding of the mechanisms involved in regulation by surface receptors within the CD2 family on cytotoxic lymphocytes may result in incorrect predictions of functional outcome and potential targets being overlooked. In common, these receptors contain an immunoreceptor tyrosine based switch motif (ITSM) which binds the intracellular adaptors, SAP and EAT-2. We shall continue to focus on CD244 because it is unique among these receptors having the greatest number of ITSM and a heterophilic cell surface ligand, CD48. These characteristics predict that CD244 will have the greatest impact on SAP and EAT-2 mediated signalling and potential for manipulation at the cell surface. There are data to indicate that in addition to binding the SRC kinase, FYN, which is important for propagating phosphorylation, SAP and EAT-2 recruit downstream effector enzymes. We have identified the phospholipase, PLC-gamma 1 as a direct binding partner for EAT-2. The aims of this study are to determine: 1. The functional dependence of SLAM family receptor signalling on intracellular ligands. We have excellent preliminary data to show that SLAM family receptor signalling in a natural killer cell line is dependent on PLC-gamma 1 and signalling through other receptors is not. We shall test the dependency of SLAM family signalling on PLC-gamma 1 and compare the relative importance of this putative EAT-2/PLC-gamma 1 pathway with SAP mediated signalling pathways in human NK and CD8+ T cell lines and in primary cells. 2. The hierarchy of intracellular ligands for SLAM family receptors. To complete our systematic analysis we will analyse binding of tandem SH2 domains of phosphotyrosine phosphatases and PLC-gamma 1 to tandem motifs in the tails of receptors and the adaptor, EAT-2 respectively. Functional dependency on ITSM and intracellular ligands will be tested using lentiviral transduction of mutated receptors and shRNA. Functional assays will include cytotoxicity assays and cytokine secretion. Levels of receptors and intracellular ligands will be monitored by flow cytometry and western blotting. Biochemical methods will include measurements of direct interaction between recombinant SH2 domains and phosphorylated peptides, an assay we have previously shown mimics interactions on native cytoplasmic tails and correlates with function. This project will establish the significance of a novel potentially important signalling pathway through EAT-2 and PLC-gamma 1 allowing rational evaluation of potential of SLAM family members in cancer immunotherapy.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Identifying novel biomarker-driven therapeutic strategies for castration-resistant prostate cancer
Funder: Cancer Research UK

Abstract: BACKGROUND: Abiraterone and MDV3100 are effective treatments for castration-resistant prostate cancer (CRPC). However, 30-50% of CRPC patients have primary resistance and all patients will ultimately become resistant. OVERALL AIMS: To define genetic aberrations and molecular phenotypes that associate with clinical resistance to abiraterone and/or MDV-3100.To develop novel, therapeutic strategies and predictive biomarkers for CRPC.METHODS:AIM 1: To characterise clinical resistance to abiraterone and/or MDV-3100, sequencing of plasma nucleic acids and fluorescence in situ hybridisation and immunofluorescence on tissue biopsies and circulating tumour cells (CTC) will be used to study genetic aberrations of the androgen receptor (AR) signalling axis and changes in ERG and AR expression at progression on MDV3100/abiraterone. Differential gene expression in patient-matched pre- and post- abiraterone/MDV3100 tumours will be integrated with 1) expression and copy number datasets from prostate cancer patients pre- and progressing on castration, 2) AR transcriptional signatures identified following hormone treatment of hormone-starved prostate cancer cell lines and 3) lists of AR-binding targets identified in AR ChIP-seq assays. AIM 2: To develop novel, therapeutic strategies for CRPC, targeted and whole-genome functional high-throughput RNA-interference and compound screens will be performed. LNCaP and VCaP cancer cells will be treated with the antiandrogens, MDV3100 and bicalutamide, and grown in hormone-deprived conditions that result in a 20% reduction in survival. Determinants of sensitivity or resistance will then be identified. Initial screens will detect changes in cell inhibition but secondary selection will choose genes that are differentially expressed in Aim 1 and low-throughput evaluation will identify candidates that reproduce clinically relevant phenotypes. Combination strategies will be identified and druggable targets will be considered for a drug discovery programme. AIM 3. To develop predictive biomarkers, genes identified in Aim 2 will be studied in tissue, CTC and plasma nucleic acids and integrated with analyses of underlying gene rearrangement status and aberrations of the AR axis to evaluate their association with clinical outcome. Robust biomarkers will be developed to test prospectively in early clinical trials of therapeutic strategies developed in Aim 2. Biomarker panels identifying primary and secondary resistance to abiraterone/MDV3100 will be developed for prospective clinical evaluation. FUTURE OPPORTUNITIES:It is envisioned that this work will lead to novel molecular diagnostics and therapeutics that could improve the outcome of patients with CRPC, an area of unmet medical need.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Improving cancer therapy by systemic administration of oncolytic viruses
Funder: Cancer Research UK

Abstract: Background: We have shown that oncolytic viruses (OV) such as reovirus exert their anti-tumour effects by activating anti-tumour immunity, as well as by directly killing cancer cells. Reovirus is well advanced in the clinic, and our own laboratory and patient data has shown that cells in the blood can protect reovirus from neutralization following intravenous injection for delivery to tumours. Moreover, such carrier cells can be activated by reovirus to acquire immune-mediated anti-tumour effector function._x000D_ _x000D_ Aims and Objectives: Within three specific aims, we will develop strategies to improve direct cytotoxic and immune-mediated therapy for melanoma and colorectal cancer by OV following systemic administration. The first two aims focus on tumour-targeted delivery of reovirus. Aim 1 seeks to enhance the protected delivery of reovirus to tumours by boosting the number of potential carrier cells (granulocytes, monocytes, lymphocytes, dendritic cells) in the blood, using ‘cell mobilizing drugs’ (granulocyte or granulocyte-macrophage colony stimulating factor, interleukin-2 and FMS-like tyrosine kinase 3 ligand). We will also test for activation of anti-tumour immune effector function in these cells by reovirus carriage, and for analogous activation by reovirus of normal resident liver immune cells which the virus accesses in vivo. Aim 2 further addresses improvement in immune- and vascular-mediated systemic reovirus therapy via combinations with immunomodulatory histone deacetylase inhibitors or chemotherapy, including in the context of vascular endothelial growth factor-secreting tumours. In Aim 3, we will test an alternative lymphoid-targeted systemic OV strategy, using ‘Viral Expressed Epitope Library’ (VEEL) vaccines. Vesicular stomatitis virus (replication competent or single cycle), will be used as a viral platform to express a full cDNA library derived from melanocyte/melanoma, autologous/allogeneic/xenogeneic tissue to treat melanoma. Here, the OV acts as an adjuvant to stimulate immune priming against multiple, undefined tumour-associated antigens expressed by the VEEL vaccine._x000D_ _x000D_ Methods: Established murine in vivo and human in vitro preclinical models of therapy and anti-tumour immune priming will be used. These include readouts of purging of metastatic lymphoid metastases in mice, and experiments using tissue and blood from patients undergoing cancer surgery. This breadth of analysis is critical for testing whether common principles apply across different model systems, and underpins informed clinical translation._x000D_ _x000D_ How the results will be used: The results of this work will be used to further optimize the use of systemic OV agents and inform the next generation of biological endpoint and therapeutic trials to build on our established clinical platform.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Predicting the impact of HPV vaccination on cervical cancer: the interaction with screening
Funder: Cancer Research UK

Abstract: Background: Since HPV vaccination was introduced in 2008 around 80% of schoolgirls offered the vaccine in the routine programme have been fully immunised. A similar proportion of women are regularly screened against cervical cancer. Who are the unimmunised girls? If many of them go on to regularly default or not attend screening, then the impact of vaccination will be far less than has been predicted by mathematical models, which, to date, have all assumed that these are not related. _x000D_ Aims & Objectives: This study will analyse data on the first vaccinated cohorts to: 1) ascertain if those girls who do not receive a full course are more likely to have risk factors for HPV; 2) explore the attitudes to screening and perceptions of protection from the vaccine in 15-17 year old girls; 3) estimate the levels of screening uptake and factors (e.g. socio-economic) affecting uptake in the first women who will have been offered vaccine and screening ; and 4) predict the impact of vaccination on the incidence and distribution of cervical cancer taking account of these heterogeneities._x000D_ Methods: Four inter-related sub-projects will be undertaken. A) The health records of the first two cohorts of girls routinely vaccinated (aged 14-16 in 2011) will be examined to determine individual-level HPV risk characteristics of unvaccinated girls. Factors such as area of residence, socio-economic status, ethnicity and indicators of early sexual activity (e.g. oral contraceptive use) will be examined for their relationship with HPV immunisation. B) Details on sexual behaviour, risk perceptions and attitudes to screening by HPV vaccine status will be analysed through a school-based survey of 15-16 year old girls. C) A record-linkage study will be performed using Welsh data to ascertain the uptake of screening in vaccinated cohorts and factors affecting non-response with both programmes. D) An individual-based transmission model will be developed capable of taking into account the interactions between the vaccine uptake and risk factors for HPV infection and disease. Key model parameters will be based on the findings of parts A-C. _x000D_ How the results of this research will be used. Early indications of risk-factors for HPV infection and screening uptake in unvaccinated girls are essential to help improve equity of uptake. Combining this with a mathematical model provides a tool that can be used to predict the incidence and distribution of disease and assess changes to policy.


Research activity codes: 4.3 INFLUENCES AND IMPACT;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: Cancer waiting times and its effect on survival: analysis by deprivation and ethnic groups
Funder: Cancer Research UK

Abstract: Background: Cancer survival is lower in the UK compared to other European countries. The 2000 NHS Cancer Plan was implemented with key aims of reducing waiting times and inequalities and improving survival. Initiatives to reduce waiting times have failed: delays and inequalities persist. Survival gaps between ethnic and deprivation groups continue despite the Cancer Plan. Reasons for differences in waiting times and effects of these on survival remain unknown._x000D_ _x000D_ Aims and objectives: This study will investigate the impact and potential preventability of socio-economic and ethnic inequalities in cancer care. Objectives are to determine the contribution of waiting times to inequalities in cancer survival, to explore reasons why inequalities in waiting times arise and to investigate potential interventions to reduce waiting times in patients’ cancer journeys. These objectives will cover breast, colorectal, lung and prostate cancers and non-Hodgkin’s lymphoma._x000D_ _x000D_ Methods: A mixed-methods approach will be used: a quantitative investigation will determine inequalities in waiting times and their effect on survival; a systematic review will identify interventions to reduce waiting times and inequalities in waiting times; a qualitative investigation will explore explanations for the quantitative findings and the applicability of interventions identified in the systematic review to NHS Cancer pathways. Data for cancer cases diagnosed between 1996 and 2010 will be obtained from Cancer Registries, Hospital Episode Statistics, Office of National Statistics and the General Practitioners Research Database. Databases will be linked and analyzed using multivariable linear regression and excess risk modeling. A systematic review will summarize information on existing interventions. It will follow the Cochrane Collaboration methodology and involve searching through Medline, EMBASE, the Cochrane database and grey literature archives. Results will be summarized using a narrative empirical synthesis. _x000D_ The qualitative investigation will involve semi-structured interviews with 25-30 doctors to elucidate how and why they think inequalities in referral-to-treatment waiting times and survival arise and views on existing interventions. Purposive sampling will include both GP and hospital specialists for cancer sites for which a range of inequality patterns are shown in the quantitative data. Data will be subject to thematic analysis. _x000D_ _x000D_ How the results of this research will be used: The study will inform GP commissioners, hospital trusts, cancer care planners and charities on the magnitude of and reasons for inequalities. Data on causes of inequalities and possible interventions will enable government agencies and charities to focus resources and develop strategies addressing the specific needs of minority and economically deprived groups.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS