NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of DNA repair in the aetiology of bladder cancer and its response to radiotherapy and combined modality treatments
Funder: Cancer Research UK

Abstract: To investigate the mechanisms underlying the non-homologous end-joining defective/microhomology-mediated end-joining phenotype seen in muscleinvasive bladder cancer, and to exploit this clinically in combined radiotherapy/biological treatments. To investigate expression of the DNA damage signalling protein MRE11 as a potential biomarker for prediction of outcome following radiotherapy and chemotherapy, and to establish the role of other such biomarkers. This should ultimately allow patient selection for optimal bladder cancer treatment, thus increasing overall cure rates. To establish which DNA repair gene germ-line variants implicated in bladder cancer risk would allow identification of high-risk idividuals, who would benefit from prophylactic intervention with targeted screening and lifestyle intervention to minimize bladder cancer mortality.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Vascular Proteomics
Funder: Cancer Research UK

Abstract: Angiogenesis is the process of formation of new vessels from pre-existing ones. It is a very important mechanism involved in cancer development. Indeed, many tumours need oxygen and nutrients provided by the blood to progress, and exploit the blood flow to metastasise. Endothelial cells constitute the first layer of the vessel wall and are the major cell players in the angiogenic process. Endothelial cells orchestrate a multitude of biological processes that trigger the formation of new and mature vessels – they sprout, digest and migrate through the extracellular matrix, change morphology and recruit mural cells. A better understanding of the regulation of these processes will be helpful to identify new targets for pro- and anti-angiogenic therapy in cancer. High accuracy mass spectrometry (MS) in combination with quantitative approaches, such as SILAC (stable isotope labelling with amino acids in cell culture), is a key technology to perform in depth proteomic studies of cells and tissues. With this technique it is possible to identify and quantify thousands of proteins and post-translational modifications, for example phosphorylations, in single experiment. In our lab, we apply state-of-the-art MS-based approaches (LTQ-Orbitrap Velos) in combination with SILAC to study the complexity of the molecular mechanisms regulating endothelial cells, in vitro and in vivo, during angiogenesis in cancer. In particular, we are interested in characterising how the (tumour) extracellular environment affects endothelial cell signalling.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Signalling Networks in Cancer Group
Funder: Cancer Research UK

Abstract: driver mutations: a roadmap for the identification of protein kinases involved in cancer. Cancer genomic studies have illuminated the complex nature of cancer and made it apparent that there are numerous and distinct mutations present in every tumor. This information can be used to identify novel common and convergent molecular mechanisms employed by cancer cells to promote the stepwise process of tumor formation. Cancer genomic sequencing studies can successfully identify pathways that are inactivated or constitutively activated, and experimental analysis of signalling proteins with frequent mutations in cancer, such as B-RAF and PIK3CA, demonstrates they play a casual role in tumorigenesis. Going forward new approaches must be developed to identify proteins that are mutated at a lower frequency yet are still crucial for tumorigenesis and thus harbour somatic driver mutations. To this end we have used a bioinformatics approach to identify novel or understudied kinases where all or a vast majority of somatic and germline mutations are predicted to be driver mutations and therefore likely alter the function of a kinase so that it is essential for tumor evolution. A major focus of our group is to investigate if the reported cancer mutations in top candidate kinases play a role in cell transformation and tumorigenesis, with the potential of identifying new target pathways for therapeutic intervention. We will also focus on studying the PKC family of kinases, which have been intensely investigated for over 25 years in the context of cancer. Historically, this arises from the discovery of PKC as the receptor for the tumor-promoting phorbol esters, which suggested that activation of PKC by phorbol esters promoted tumorigenesis induced by carcinogens. However, this interpretation is now open to question, since long-term treatment with phorbol esters is known to initiate degradation of PKC, thus down-regulating its activity. The second aim of our research will focus on determining if PKC mutations inhibit or activate PKC isozymes and how this complements other mutations acquired in a given tumor, such as activating K-Ras mutations.


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

Abstract: Overview Tumour initiation and progression result from inappropriate activation of intracellular signalling cascades. Rho-like GTPases are molecular switches in signalling pathways that regulate actin cytoskeleton organisation and gene transcription. In this way, Rhoproteins influence cell morphology, adhesion, motility, as well as cell cycle progression and cell survival. Rho proteins are essential for Ras-mediated in vitro transformation. Recently, data has emerged to directly implicate Rho proteins in tumour initiation and progression in vivo. Employing murine models, our group will determine the contribution of Rho-like molecules to the formation of various tumour types and will concentrate on identifying signalling events downstream of Rho proteins that modulate tumour susceptibility.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/12/002: 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.
Funder: Cancer Research UK

Abstract: Prognostic stratification and treatment decisions for patients with neuroblastoma are critically dependent on functional imaging. [123I]mIBG scintigraphy, the international standard technique, suffers from shortcomings including poor resolution and a lack of ability to accurately quantify results. There is a pressing need for a targeted imaging modality that can achieve high sensitivity and specificity for tumour cells, deliver the excellent spatial resolution required to precisely localise small disease foci, offer reliable and reproducible quantitative assessment of disease extent, and enable better evaluation of the increasing number of potential new therapies for neuroblastoma. We propose an entirely new targeted imaging technique for neuroblastoma, using the positron-emitter [124I]mIBG as a novel PET radiotracer. We hypothesise that [124I]mIBG PET/CT will improve diagnostic accuracy compared to [123I]mIBG scintigraphy and reduce the number of investigations required for disease evaluation. In this proof-of-concept study we will prospectively assess the performance of these two modalities, in the assessment of metastatic neuroblastoma in patients with both newly-diagnosed and relapsed disease. We will optimize a semi-quantitative scoring method for [124I]mIBG PET/CT, to facilitate comparison with [123I]mIBG scintigraphy and compare scores, with SUVmax/SUVmean as alternative semi-quantitative methods. Results will be presented to the NCRI Children's Cancer and Leukaemia Clinical Studies Neuroblastoma Subgroup for wider evaluation. Last updated 14/09/2010


Research activity codes: 4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/11/003: A Phase I/IIa trial of AZD4547, an FGFR inhibitor, in combination with cisplatin and capecitabine (CX) in patients with locally advanced gastro-oesophageal cancer
Funder: Cancer Research UK

Abstract: Background_x000D_ Genetic modifications of the FGF receptors, including amplifications, translocations, and mutations, have been described in a range of tumours, including polysomy or amplification of FGFR2 in approximately 30 – 40% of gastric cancer patients. Pre-clinical data indicate that the presence of these changes can confer sensitivity to FGFR inhibitors. AZD4547 is a potent and selective inhibitor of fibroblast growth factor receptor (FGFR) 1, 2, and 3 receptor tyrosine kinases. Cisplatin and capecitabine are established agents that are given in combination in the treatment of a number of cancers, including advanced gastro-oesophageal cancer. However, clinical outcome with this regimen remains disappointing in patients with advanced gastro-oesophageal cancer, with a median overall survival of 9 – 11 months._x000D_ _x000D_ Specific Aims_x000D_ The aims of the phase I part of this study are to determine the safety, tolerability, and maximum tolerated dose of AZD4547 when administered in combination with cisplatin and capecitabine (CX) in patients with advanced refractory cancers. Pharmacokinetic (PK) and pharmacodynamic (PD) studies will also be performed. The specific aims of the Phase IIa part of the study are to compare the effects of AZD4547-CX with CX on progression-free survival, objective response rates, overall survival, and pharmacodynamic studies, when administered to patients with locally advanced or metastatic gastro-oesophageal adenocarcinoma and with FGFR2 polysomy or amplification (FISH 4/5 or FISH 6)._x000D_ _x000D_ Study Summary_x000D_ Eligible patients for the Phase I component of the clinical trial will receive one of escalating doses of AZD4547 given twice daily in a continuous oral administration schedule in combination with a fixed dose of Cisplatin (80 mg/m2 intravenously) and Capecitabine (1000 mg/m2 orally twice daily on days 1 – 14) three weekly with a “rolling six” dose escalation design. Eligible patients for the Phase IIa part of the study will be randomised to receive either the recommended dose of AZD4547 (as determined in the Phase I component of the study) in combination with CX three-weekly, or to receive CX three–weekly. Patients will receive up to 6 cycles of chemotherapy and patients who receive AZD4547-CX and who have evidence of response or stable disease after 6 cycles of treatment can continue to receive AZD4547 monotherapy twice daily in a continuous oral administration schedule until disease progression or until unacceptable toxicity, or patient decision to discontinue. The primary endpoint will be progression-free survival


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CCLG Tissue Bank
Funder: Cancer Research UK

Abstract: The original aim of the Children’s Cancer and Leukaemia group (CCLG) Tumour Bank was to provide research groups with access to material from solid paediatric tumours since they are relatively rare, with small numbers available in any individual centre. The CCLG Tumour Bank has been running since 1998 and currently operates as a ‘virtual bank’, with tumour samples stored locally in the 21 participating CCLG Centres but with central registration, management and release of samples coordinated from the CCLG Data Centre, in Leicester. It was agreed by the CCLG Executive that centralisation would improve the effectiveness of the Tumour Bank. Newcastle was the centre chosen to host the centralised CCLG Tumour Bank and will host the existing historical collection centrally and providing a centralised bank for the prospective collection of tumour samples and bloods from the 21 CCLG Treatment Centres across the UK and Ireland. The bank will also be responsible for distributing the samples for academic research according to the scientific decisions made by the CCLG Biological Studies Steering Group (BSSG), chaired by Dr Keith Brown. The CCLG Data Centre (Leicester) will continue to host the bank database (containing linked clinical data) and will identify the samples to be released to researchers, after approval by the BSSG. The BSSG will also provide overarching governance to the bank. Currently, the Tumour Bank holds over 9,500 samples collected from 7,268 patients. Funding has been provided to provide infrastructure costs for the bank, to transfer existing samples to Newcastle and to establish protocols for the transfer of samples collected prospectively in the future.


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/11/004: RADICAL a First in Man Phase I/IIa study of AZD4547, an FGFR inhibitor, in combination with a non-steroidal aromatase inhibitor (anastrozole or letrozole) in ER+ advanced breast cancer patients
Funder: Cancer Research UK

Abstract: Background to the proposal Many women with advanced oestrogen receptor positive (ER+) breast cancer become resistant to treatment with nonsteroidal aromatase inhibitors letrozole and anastrozole. Subsequent therapy is either with the steroidal aromatase inhibitor exemestane offered with or without the rapalogue everolimus or with a selective oestrogen receptor down-regulator such as fulvestrant prior to cytotoxic drugs. The latter are not curative and so there is considerable interest in developing approaches that might reverse resistance to hormone and/or cytotoxic based therapies. Recent pre-clinical work has demonstrated that inhibition of fibroblast growth factor receptor (FGFR) signalling might reverse resistance to both these therapies in several cancer types including breast cancer. Specific aims of the research 1) To determine if the FGFR inhibitor AZD4547 when added to letrozole or anastrozole can reverse resistance to either agent 2) To test a number of factors which could predict benefit as well as collecting FISH amplification data on FGFR1 Summary of proposed study Initially, we will undertake a phase Ib study in advanced ER+ breast cancer patients to determine the optimum safe dose of AZD4547 in combination with letrozole or anastrozole. We will then perform a Phase IIa trial where ER+ breast cancer patients that have shown resistantance to letrozole or anastrozole at some time in thier treatment of breast cancer will continue or restart the NSAI which they have progressed on: either anastrozole or letrozole but together with twice daily AZD4547. The primary end point will be change in tumour size at 12 weeks.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/11/005: SCART - Phase I/II study of the oral MEK inhibitor Selumetinib (AZD6244) in Combination with Highly Active Anti-Retroviral Therapy (HAART) in Kaposi's Sarcoma (KS)
Funder: Cancer Research UK

Abstract: Background Kaposi's sarcoma (KS) is a malignant vascular tumour. It is the commonest AIDS-associated cancer and is linked to co-infection with human herpes virus-8 (HHV-8) and HIV-1. HHV-8 encodes several proteins including viral interleukin-6 (vIL-6) and viral G-protein coupled receptor (vGPCR). These up-regulate the mitogen-activated protein kinase (MAPK)/Ras/Raf/MEK/ERK pathway, which promotes cell survival and cell proliferation. This pathway is up-regulated in many cancers and in KS has been shown to stimulate the expression of angiopoeitin-2 (Ang-2), a pro-angiogenic factor, which further promotes the growth of KS tumours. Thus the Ras/Raf/MEK/ ERK pathway is an attractive target for treatment in KS. Localised KS often responds to highly active anti-retroviral therapy (HAART) but advanced lesions may require cytotoxic chemotherapy. However relapse is common and alternative treatment options are required. Selumetinib (AZD6244 Hyd-Sulphate) is an orally bioavailable selective inhibitor of MEK 1/2. It is minimally active against other kinases. We will test selumetinib in combination with HAART in patients with AIDS-associated KS. The trial will be open in selected ECMC centres. Primary objectives - to identify a safe dose for selumetinib in combination with HAART. - to establish evidence of efficacy using objective response rate. Secondary objectives: - to describe the pharmacokinetics and pharmacodynamics of selumetinib in combination with HAART, including the effects of selumetinib on HAART metabolism. Study design - an open-label multi-centre phase I/II trial. In phase I, patients will be recruited to establish the dose, safety, pharmacokinetics and pharmacodynamics of selumetinib in combination with HAART in KS, using a 3 + 3 fixed dose escalation algorithm. In phase II, efficacy will be assessed in patients recruited to the recommended phase II dose. Efficacy will be assessed in a single arm patient cohort by objective tumour response using the AIDS Clinical Trials Group (ACTG) criteria.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Belfast CR-UK Centre (Clinical Training Account)
Funder: Cancer Research UK

Abstract: Clinical training associated with: As one of the first centres, the Belfast Cancer Research UK Cancer Centre will help set the pace for national and international progress in cancers of the bowel, oesophagus and breast. It will also concentrate on pioneering the latest techniques in radiotherapy, improving cancer diagnosis and developing new, more effective drugs. The Centre aims to be a world leader in developing treatments tailored to individual cancer patients based on understanding the biology of the disease and how that varies among patients. Collaborations - a cornerstone of this virtual Centre - will focus on identifying new targets for cancer drugs, understanding how genes can help predict which treatment will be most effective, and developing specific new treatments that have fewer side effects. The Centre is a partnership between Queen's University Belfast, the Northern Ireland Health and Social Services Central Services Agency's Research and Development Office, Belfast Health and Social Care Trust and Cancer Research UK.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Dundee Cancer Research UK Centre (Non-Clinical Training Account)
Funder: Cancer Research UK

Abstract: Non-clinical training associated with: The Dundee Cancer Research UK Centre brings together scientists, doctors and nurses from Dundee and Tayside. Collaboration is the key to the success of the Centre, ensuring that cutting-edge research brings benefits to patients in and around the city. The Centre is a partners between Cancer Research UK, the University of Dundee and NHS Tayside. Researchers at the Dundee Centre will focus on skin, breast and bowel cancers. They will also build on their world-class research into cancer surgery to develop more effective ways of using this cornerstone treatment. Scientists in Dundee are internationally recognised for their work into cell biology û studying the key processes that take place in healthy cells and how these go wrong in cancer. They are also investigating genetic faults that increase the risk of cancers such as bowel cancer, and finding out how some genes can influence a patientÆs response to treatments. A key aim of the Dundee Centre is to encourage the expansion of translational research in the city û using scientists' discoveries in the lab to design new ways to diagnose and treat cancer. For example, researchers investigating melanoma skin cancers are exploring why some patients become resistant to treatment, aiming to combat this problem and save more lives. Another strength in Dundee is clinical research using imaging to improve surgical techniques for several types of cancer. Through clinical trials, these innovative new treatments are being offered to patients in Dundee and Tayside. Staff at the Dundee Centre will also improve training for cancer nurses as well as working with local people to raise awareness of disease symptoms and ways to reduce their risk. Grants support a variety of training projects - where available coding is done on the basis of these individual pieces of research.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: Imperial Cancer Research UK Centre (Clinical Training Account)
Funder: Cancer Research UK

Abstract: Clinical training associated with: The Imperial College Cancer Research UK Centre unites the largest NHS trust in the UK with world-class research expertise to tackle cancer. At the heart of the North West London Cancer Network, the Centre is at the forefront of cancer research and patient care. The Centre is a partnership between Cancer Research UK, Imperial College London and Imperial College Healthcare NHS Trust, which has five hospitals in the capital. The Trust is also designated as the UKÆs first Academic Health Science Centre, transforming cutting-edge research into benefits for patients as fast as possible. Researchers at the Centre have a particular interest in breast and bowel cancers, and leukaemia. They also specialise in prostate, ovarian and lung cancers, as well as several other types of cancer. Cancer surgery is a high priority at Imperial College, and doctors here are leading the world in developing robotic and keyhole surgery. Researchers at the Centre are also using state-of-the-art technology to develop and test the latest radiotherapy and laser therapy techniques. Another area of expertise is cancer imaging. Scientists at the Centre are developing more accurate ways to track the growth and spread of the disease within the body, and to see how well treatment is working. Imperial also has great strengths in the area of cancer biology, and developing and testing new cancer drugs. Research at the Centre will reveal more about how to treat cancer on an individual level, helping doctors to select the most appropriate treatment based on the genetic makeup of a personÆs tumour. The Imperial College Cancer Research UK Centre also includes the St MarkÆs Family Cancer Group, which is investigating the causes and prevention of bowel cancer. Researchers at the Centre are also investigating more effective screening techniques, to help doctors diagnose bowel cancer earlier and save lives. Finally, Imperial College is a world-famous medical school, attracting some of the brightest and best scientists and doctors from around the world. The Centre will provide a fertile environment for training the cancer workforce of the future, bringing benefits to patients now and for years to come. Grants support a variety of training projects - where available coding is done on the basis of these individual pieces of research.


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS