NIHRDataInsights/HRCSData huggingface dataset:
Title: Long-term cancer risks in relation to radiation exposures received due to CT scanning in children and young adults - an extension to the existing UK cohort
Funder: Cancer Research UK

Abstract: Background Since entering clinical service use in the 1970s as an alternative to standard X-rays and ultrasound, examinations using computed tomography (CT) have rapidly become an indispensable, sometimes life-saving diagnostic tool, with still increasing clinical applications. Whilst the immediate benefit to the individual patient of having a CT examination can be substantial, the relatively high radiation doses associated with CT have given rise to growing concerns from a public health perspective. in particular, due to a possible increase in future cancer risk. Studies of exposed populations indicate that children are generally more sensitive to the adverse health effects of radiation than adults. In addition, they have a longer life-span to express any effect and, because of their smaller mass, children may receive higher doses to specific organs from these procedures if examination protocols are not adapted. We have recently reported increased risks of leukaemia and brain tumours following CT, but need a larger cohort and lengthier follow-up to study these and other cancers in more detail. Aims To extend the existing cohort of patients who received CT scans up to the end of 2011, to evaluate the pattern of use of CT over time, to derive individual estimates of organ doses and evaluate further radiation-related risk of cancer in this cohort. Methods A cohort of over 230,000 patients, aged less than 22 years, undergoing CT examination between 1985-2002 for the first time in a range of NHS hospitals across the United Kingdom has been established. Further data will be collected from Radiology departments across the UK to extend the cohort to include over 450,000 individuals and include exposure data up to the end of 2011. Additional cases will be matched with data on the NHS Central Register to identify patients who died or developed cancer. Absorbed doses will be estimated per scan and cumulative organ doses calculated. Results The results will allow an assessment of CT usage in more recent years in this population as well as giving much greater statistical power to analyse the risks in relation to rarer cancer outcomes and subtypes than we can currently assess. As with our recent Lancet paper, we will ensure a balanced approach to presenting any significant increased risks in relation to the radiation doses received, in particular with regard to the likely benefits of CT scans when used in a justified fashion.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS
Title: CRUK/12/042: A phase I/randomised phase II study in metastatic castration resistant Prostate Cancer of AZD5363 In combination with Docetaxel and prednisolone chemotherapy (ProCAID)
Funder: Cancer Research UK

Abstract: Background: Unfortunately, men with metastatic castration resistant prostate cancer (mCRPC) have a poor prognosis and most will die of the disease. Their median survival is 2-3 years. We therefore have a pressing need to improve current treatment options. Docetaxel/prednisolone chemotherapy (DP) modestly prolongs overall survival after initial treatment with hormonal therapies becomes ineffective. AKT pathway activation is highly prevalent in mCRPC and is associated with disease aggressiveness and clinical resistance to docetaxel. AKT inhibition in mCRPC has a strong pre-clinical rationale both as a single agent strategy and as a means to restore docetaxel responsiveness and so warrants clinical evaluation. Primary aim: To determine if the addition of the AKT inhibitor AZD5363 to DP prolongs progression free survival (PFS) in mCRPC. Secondary aims: To explore the effect of AZD5363 when added to DP on secondary endpoints of overall survival, bone pain changes, PFS when excluding biochemical alone progression, biochemical response rates, safety and toxicity profiles and pharmacokinetics. To undertake collection of translational research samples. Methods: This clinical trial will have an initial single arm, open label, phase I dose escalation component to establish a safe dose of AZD5363 to combine with full dose DP. Following this, 130 patients with mCRPC, for whom DP is appropriate therapy, will be randomised (1:1) in a double blind fashion to either oral AZD5363 or matching placebo until confirmation of disease progression combined with up to 10 cycles of DP every 3 weeks. Progression status will be determined by investigator assessment using the Prostate Cancer Working Group (PCWG2) criteria. How the results of this research will be used: If we are able to establish that the addition of AZD5363 to DP chemotherapy prolongs PFS according to pre-determined statistical criteria, and with an acceptable safety profile, then we would proceed to a phase III clinical trial of this combination to determine the effects on overall survival.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Radiotherapy Physics Reseach Group
Funder: Cancer Research UK

Abstract: Translation of radiotherapy from the laboratory to the clinical setting requires close collaboration with clinical teams The ultimate goal of my team is to harness technical advances in both medical imaging and radiation delivery to provide improved radiotherapy for individual patients. Recent advances have greatly improved the accuracy and reproducibility of radiotherapy delivery, with improved targeting of radiation to the three-dimensional structure of tumours whilst sparing normal tissue; in parallel with this has been an improved understanding of the biology and behaviour of tumours in real patients. The focus of tailored radiotherapy is to better deliver radiation to patients based on their own biology. One avenue of research involves monitoring response to treatment so that it can be modified in real time according to patient response, using medical imaging techniques to advance biologically-adaptive radiotherapy.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/13/003 VIBRANT A Phase I clinical trial with VEGFR antagonist vandetanib combined with 131I-mIBG radiotherapy in patients with neuroendocrine tumours, advanced phaeochromocytoma and paraganglioma
Funder: Cancer Research UK

Abstract: Background Pheochromocytomas (pheos) and paragangliomas (PG) are classed as neuroendocrine tumours (NETs), they are rare with an incidence of 1-2 per 1 million population. The standard first line therapy for metastatic (inoperable) disease is 131I mIBG radionuclide therapy, used in over 80% of UK centres. Although there is a lack of large RCT evidence, response rates of 30-47% are reported. Up to 24% of pheos and PG develop as a result of inherited mutations in VHL, RET, SDHB/D and NF1. These pathways are also known to be disrupted in sporadic tumours. Expression array and immunohistochemistry studies have demonstrated that Hypoxia Inducible Factor activiation (including a pseudo-hypoxic drive in patients harboring SDH mutations) and over-expression of VEGF is observed in these tumours. drugs targeting angiogenic pathways such as sunitinib have been reported to show activity in PG and Phase II trials of such agents are ongoing. Vandetanib is an oral inhibitor of VEGFR, EGFR and RET, and therefore potentially has activity in in this tumour type. We therefore hypothesize that a combination of vandetanib with I131I mIBG therapy could potentially have synergistic interaction leading to improved clinical outcomes. Aims To conduct a Phase I trial of vandetanib and 131I mIBG radionuclide therapy in patients with advanced pheo/PG to determine the maximum tolerated dose, safety and tolerability of the combination. In addition, we propose to assess preliminary evidence of anti-tumour activity, and explore predictive and response surrogate biomarkers of response to the combination using circulating and imaging biomarkers. Methods Conduct a Phase I open-label, dose escalation study of vandetanib and 131I mIBG in patients with advanced pheo/PG. We propose to use a fixed dose of 131I mIBG based on whole body radiation dose of 2Gy with 3 dose levels of continuous vandetanib (100, 200 and 300mg), dose escalation performed using the Modified Continual Reassessment Method (mCRM). 131I mIBG will be administered in 3 monthly cycles. Dose limiting toxicities will be defined during the first 3 month period between 1st and 2nd cycles of I131-mIBG. In addition, correlative studies using circulating endothelial cells, plasma angiogenesis and inflammatory biomarkers, and functional imaging with diffusion-weighted MRI and 18F-DOPA will be conducted. How the results of this research will be used We aim to conduct a national, multi-centre, randomised Phase II trial exploring the efficacy of the combination of vandetanib and I131 mIBG.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: NCRI: PET Core Lab
Funder: Cancer Research UK

Abstract: Positron Emission Tomography (PET) is increasingly being used as an imaging biomarker and promises to facilitate the rapid assessment of new cancer therapies. In order to acquire sufficient number of scans to obtain an adequate statistical power, many trials involving PET require data to be acquired at a number of different scanning sites. PET is a very complex imaging modality with many potential sources of human, technical and biological variation/error that can reduce the accuracy and precision of the results of an individual scan. The greater this variation is across all the scans contributing to a given study, the more scans will be required to reliably detect an effect. Carefully controlling protocols so that these biological variations/errors are kept to a minimum is therefore essential if PET is to be used most effectively, and the establishment of networks of accredited scanning sites operating to rigorous standards is now recognised as the way to achieve this The ‘NCRI PET Clinical Trials Network’ (PCTN) currently consists of ~30 accredited independent sector, university and NHS PET scanning sites across the UK. The hub of the PCTN is the ‘Core Lab’ based at St Thomas’ PET Centre. The role of the Core Lab is to manage the scanning site accreditation process, quality control prior to and during the trial and transfer of PET image data between scanning sites and the central analysis site. A principal investigator (PI) wishing to undertake a PET trial therefore only has to interact with the Core Lab, rather than having to set up, solve and manage IT, communication, protocol, quality control (QC), data transfer and technical issues etc. with the many accredited sites taking part in the trial. Throughout the course of this 3 year project, in addition to continuing and expanding the number and types of trial co-ordinated by the Core Lab, other areas of development will also be investigated including international harmonization of standards, early phase PET studies, centralised data analysis and links to industry funded PET trials.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Exploiting chemical genetics to investigate the control of microtubule dynamics by mitotic kinases
Funder: Cancer Research UK

Abstract: Background: Changes in dynamics of microtubule assembly and disassembly are thought to be a source of mechanical force production to pull the replicated sister chromatids apart. The precise control of these dynamics is essential for accurate chromosome segregation and maintenance of genome stability. Disturbances in these dynamics are thought to be a major source of cancer. Understanding the molecular mechanism of mitotic force generation is of pivotal importance to unravel the fundamental biological problem of cell division. It will also help identify novel strategies to target mitotic progression that could be used therapeutically. Aims: In this proposal I will address questions arising from my previous studies. I aim to find out how Cdk1 triggers the microtubule rearrangements at the G2/M transition and investigate the impact of these rearrangements on centrosome separation. I will analyse how inactivation of Cdk1 and persistent activity of Aurora kinases trigger spindle disassembly in anaphase. Methods: I will take three different approaches to achieve these goals: 1) Visualisation of microtubule dynamics using live cell imaging in combination with chemical genetics will help clarifying the impact of mitotic kinases on the cytoskeletal rearrangements in mitosis. 2) A reverse genetic study will test the hypothesis that the microtubule severing enzyme Katanin is involved in both the G2/M and the metaphase anaphase microtubule destabilisation and is a major target of mitotic kinases. 3) Using novel strategies to purify microtubule associated proteins and native kinetochores in combination with chemical genetics and large scale quantitative proteomics. These approaches will generate new insights in the mechanisms of anaphase spindle dynamics and will identify important factors that contribute to this process. How the results will be used: The molecular engines that drive MT rearrangements in mitosis are attractive therapeutic targets to kill cancer cells. Our study will identify novel targets that we will validate for cancer therapy to initiate new translational research efforts for drug discovery.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: Cytosine-5 RNA methylation in normal and cancer stem cells
Funder: Cancer Research UK

Abstract: Stem cells maintain mammalian tissues throughout life by continuously retaining their population (self-renewal) while generating progeny (differentiation). Dissecting the regulatory pathways controlling the balance of these two states is fundamental to understanding how stem cell mis-regulation causes cancer or tissue failure. Although transcriptional regulation of stem cells is increasingly understood, virtually nothing is known about how post-transcriptional mechanisms can influence stem cell maintenance. We showed recently that stem cell self-renewal and differentiation pathways in adult skin are controlled by post-transcriptional methylation of cytosine-5 in RNA. We further demonstrated that cytosine-5 methylated RNAs mediate cellular survival after genotoxic insults, such as UV irradiation. We will now build on our discoveries and explore whether normal and cancer stem cells use cytosine-5 methylation as a post-transcriptional modification to protect themselves from apoptosis in response to genotoxic insults, including UV irradiation and cancer drug treatment regimes. Together, our research plan aims to identify novel pos-transcriptional pathways that can be targeted in therapeutic strategies to fight cancer stem cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Molecular mechanisms of kinetochore fibre stabilisation
Funder: Cancer Research UK

Abstract: Errors in mitosis can lead to gain or loss of chromosomes in the daughter cells. This is a form of genetic instability known as aneuploidy, which has a major role in cancer initiation and progression. The mitotic spindle is responsible for segregating chromosomes with high fidelity, and it is the kinetochore fibres (K-fibres) of the spindle that move the chromosomes. The K-fibres need to be stabilised optimally for accurate mitosis, but how stabilisation is achieved is very unclear and only a few details are known. The K-fibre is a bundle of 20-40 microtubules (MTs) that are held together by a meshwork of crosslinking proteins, which are thought to be important for stabilising the fibre. Ultrastructural analysis indicates that the meshwork is composed of at least four different complexes of crosslinking proteins. We have shown that one of these complexes comprises transforming acidic coiled-coil protein 3 (TACC3), colonic hepatic tumour over-expressed gene (ch-TOG) and clathrin. The aims of the fellowship are to define the molecular composition, the structure and the function of the material that holds kinetochore MTs together. To do this, the remaining crosslinking complexes in K-fibres will first be identified using proteomics, and then verified using electron microscopy. We will also determine how the proteins that make up these complexes associate with each other and how they bind to MTs. Next, the fine structure of the meshwork of crosslinking proteins in K-fibres will be detailed using advanced 3D electron microscopy. To discover how crosslinking complexes stabilise K-fibres we will rapidly (5 min) remove the crosslinking proteins and test the role of these proteins in the maintenance of K- fibre structure versus initial assembly. Finally, we will test how mitosis and K-fibre stability are altered in the cancer cell where crosslinking complexes are overexpressed or mutated. For example, the expression of TACC3 and ch-TOG is frequently altered in several tumour types and our hypothesis is that changes in K-fibre stability may contribute to cancer initiation or propogation in these cases. By the end, we will have a full molecular inventory of the proteins that stabilise kinetochore MTs and a working knowledge of how these proteins fit together in the context of the meshwork. This information will be useful to think of new strategies for therapeutic intervention or to increase the specificity of existing therapies.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Global surveillance of cancer survival (CONCORD-2)
Funder: Cancer Research UK

Abstract: Background Cancer survival varies widely around the world. Of 12.7 million cancer patients diagnosed annually around 2008, 56% occurred in low- and middle-income countries. The number will rise substantially by 2030, especially in poorer countries. All patients need access to treatment, but there is wide global inequity in access to optimal treatment. The 11 goals for 2020 set out in the UICC World Cancer Declaration include: “there will be major improvements in cancer survival in all countries”. Biennial evaluation of progress toward these goals is required, but no mechanism exists for this. Aims • To provide quantitative and directly comparable estimates of cancer survival in many countries world-wide, for 10 malignancies that are common in adults, and childhood leukaemia, using individual data from population-based cancer registries, supplied to agreed standards and analysed centrally; • To document world-wide trends in cancer survival since 1995 as the basis for systematic global surveillance of cancer survival, to enable examination of the underlying causes of survival differences, and to derive measures such as the population “cure” fraction, cancer prevalence and the number of avoidable premature deaths as a basis for informing national and global policy for cancer control. Methods CONCORD-2 will include over 160 cancer registries in 50 countries on all 5 continents for patients diagnosed between 1995 and 2009 or later with a cancer of the colon, rectum, stomach, liver, lung, breast, ovary, cervix or prostate, or leukaemia, including acute lymphocytic leukaemia in children. We will estimate relative and net survival, using life tables by age, sex, country, race and calendar year. Where data are available, we will use multi-variable excess hazard models to examine the impact of stage, diagnostic investigations and treatment on survival differences. How the results of this research will be used Cancer survival disparities and avoidable premature deaths underpin national cancer control plans, and are used to evaluate their effectiveness. The first CONCORD study “contributed to a sea-change in how national policymakers are using international comparisons to improve their health systems” (OECD). CONCORD-2 will enable us “to address the contribution of health system characteristics in explaining international differences in cancer survival.” Continuous, global surveillance of cancer survival will become a source of information for cancer patient groups and researchers, a stimulus for change in health policy and health systems, and a key metric for global surveillance of cancer control.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION
Health categories: CANCER AND NEOPLASMS
Title: Medical physics preclinical development & validation for CRUKD/12/002: a Phase II trial of 124I-mIBG in paediatric neuroblastoma
Funder: Cancer Research UK

Abstract: The aim is to provide physics support for the DDO project entitled: A phase II proof-of-concept study to compare the novel technique 124I-mIBG PET/CT to 123I-mIBG scintigraphy in patients with metastatic neuroblastoma. A series of work packages will be conducted including: Optimisation and calibration of PET/CT for [124I] semi-quantitative imaging on scanners at separate sites Cross validation of results from different centres Set up fo data handlong and image processing and analysis


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS