NIHRDataInsights/HRCSData huggingface dataset:
Title: Cancer Research UK Glasgow Centre
Funder: Cancer Research UK

Abstract: Researchers at the Cancer Research UK West of Scotland Cancer Centre are particularly focusing on bowel cancer and leukaemia, although their work will touch on many other cancer types. Scientists at the Centre also have considerable expertise in studying how cancer cells break away from a tumour and spread through the body - their work is paving the way for new treatments to halt this process. The Centre builds on Glasgow's excellent track record in developing new drugs for cancer. Scientists, doctors and nurses are working together to understand the molecular faults that lie at the heart of cancer, and find new drugs to target them. Researchers at the Centre also have the expertise to take exciting new treatments out of the lab and into the clinic, testing them in early-stage clinical trials with patients. To ensure that Glasgow continues to be a focus for cancer research for years to come, the Centre will play an important role in recruiting and training the next generation of cancer researchers. The staff at the Centre will reach out to the local community, highlighting the importance of a healthy lifestyle in cutting the chances of cancer, and how to spot the early signs of the disease (http://aboutus.cancerresearchuk.org/what-we-do/research/research-near-you/glasgow/science-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
Title: Cancer Research UK Leeds Centre
Funder: Cancer Research UK

Abstract: The Cancer Research UK Leeds Centre covers a broad range of world-class cancer research, with the goal of translating science into benefits for patients. There is a strong tradition of cancer research in Leeds. One notable example from the 1970s is Professor Craig Jordan’s University of Leeds PhD thesis on anti-oestrogens as potential therapeutic agents, which underpinned his development of Tamoxifen, the first breast cancer drug. Tamoxifen is now widely used in the treatment and prevention of breast cancer. Launched in 2010, the Leeds Centre focuses on two research themes (Cancer Immunology & Virology, Neuro-oncology). We also have the infrastructure for processing and biobanking samples to support clinical trials and laboratory studies. Engagement with the public and patients is an integral part of our activities. Our Tumour Sites: Brain Tumours Colorectal Cancer Haematological Malignancies Melanoma Urological Cancers


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Cancer Research UK Leicester Centre
Funder: Cancer Research UK

Abstract: Cancer Research UK is providing funding over three years from April 2014 and will provide staff positions to support the Centre’s infrastructure and a PhD studentship account for training the next generation of cancer researchers. The focus of the research will be on lung cancer and B cell malignancies; chemoprevention, early detection, stratified medicine and targeted therapies, and radiation research. The investment marks the latest phase in the development of the Cancer Research UK Centres network of excellence – a unique chain of research hubs that have been established across the country. This new £100m of funding will further draw together world class research and medical expertise to provide the best possible results for cancer patients nationwide. The Leicester centre is a partnership between the University of Leicester and Leicester’s Hospitals working with the Medical Research Council (MRC) Toxicology Unit at the University and the locally-based charity Hope Against Cancer. The Centre is based across the University and the Leicester Royal Infirmary.


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

Abstract: Newcastle Cancer Centre at the Northern Institute for Cancer Research Newcastle has now joined the charity's unique network of 'virtual' centres delivering world-class science and improved patient care. The new Centre puts Newcastle at the forefront of cancer research and will bring benefits to patients in the North East. The Centre is not a new building, but instead is a collaboration between Cancer Research UK, the Leukaemia Research Fund and the North of England Children's Cancer Research Fund. This will make it easier for scientists to work together with doctors and nurses, so patients can benefit from research breakthroughs more quickly. Research at the Centre will concentrate on understanding the basic biology of how and why cancers develop, with a particular focus on blood cancers, such as leukaemia, and childhood cancers. Scientists in Newcastle have an impressive track record in the discovery and development of new anti-cancer drugs. Researchers at the new Centre will focus on developing treatments that can be tailored to the genetic 'signature' of an individual cancer patient, instead of a one-size-fits-all approach. This will help to avoid unnecessary side effects and improve survival rates. Clinical trials are an important aspect of the Newcastle Centre for Cancer Research. Through this initiative, we aim for more cancer patients in the North East to be given the opportunity to take part in trials of the latest treatments.


Research activity codes: 5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Cancer Research UK Oxford Centre
Funder: Cancer Research UK

Abstract: The Oxford Cancer Research Centre is a partnership between Cancer Research UK, the University of Oxford and the Oxford Radcliffe Hospitals NHS Trust. It will help set the pace for national and international progress in the understanding and treatment of a variety of cancers, including breast, skin, urological and gastrointestinal. Collaboration will be the key to the success of the centre, as it will bring together and build on Oxford’s existing world-class research in many areas of cancer medicine, from identifying the causes of cancer to improving diagnosis and treatment of the disease. The centre will carry out research on the molecular basis of cancer, as well as work on understanding the genetic and lifestyle factors that can increase the risk of cancer. Other research strengths will include new methods for improving cancer diagnosis, and finding new ‘biomarkers’ to predict the effect drugs have on patients. The latest developments in radiotherapy and surgery will be brought together with clinical trials of new drugs, providing the best evidence to guide the treatment of cancer. Focus areas: breast, colorectal, lung, pancreas, melanoma, urological, oesophageal, brain, ovarian and haematological cancers and sarcoma; therapeutic development, bioinformatics, radiotherapy, surgery and imaging


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
Title: Cancer Research UK Southampton Centre
Funder: Cancer Research UK

Abstract: The Centre is focused upon its research strengths in Immunotherapy, Cell Biology, Medical Oncology, Surgery and Cancer Genetics, closely linked to the comprehensive clinical cancer services. http://www.southampton.ac.uk/cruk Our work in Southampton is particularly focusing on oesophageal, bowel, and head and neck cancers, as well as immunotherapy, genetics and nutrition. For example, Professor Tim Elliott and Dr Edd James are investigating how to train our immune cells to recognise and attack cancer. And Professor Peter Johnson is working to investigate how lymphoma cells survive the despite damage to their DNA so we can learn how to better treat this disease. Meanwhile, surgeon Dr Emma King is investigating why patients with certain types of head & neck cancers respond better than others to chemotherapy and radiotherapy. And Dr Simon Crabb is testing a new treatment for men with advanced prostate cancer. Our Clinical Trials Unit is working with local researchers to design and run trials that will recruit patients from across the UK. Professor Gareth Griffiths heads up the Unit team whose trials largely compare new treatments against current standard therapies. Dr Anthony Williams leads the Southampton Experimental Cancer Medicine Centre, part of our national network. We also support 13 research nurses in the city, looking after patients taking part in clinical trials of new therapies.


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

Abstract: At the UCL Centre, researchers are investigating several types of cancer, including lung, brain and gastrointestinal cancer. They’re also investigating how changes to behaviour and lifestyle can help to reduce the risk of cancer, and how to communicate these messages to the public. The UCL (University College London) Cancer Research UK Centre will foster world class research into the causes of cancers and why they develop, and use this knowledge to develop new drugs and therapies. In particular the UCL Centre will focus on the biology and treatment of blood cancers, sarcomas, brain cancer, ovarian cancer, head and neck cancer and lung cancer. Many of these cancers –particularly lung and brain- are hard to treat successfully and have poor long term survival rates compared to other common cancers. Collaboration is the key to the success of the Centre which will focus on new treatments such as gene therapy, health behaviours and drug discovery (http://www.ucl.ac.uk/cancer/about_us/cruk_centre).


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);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: Environmental control of cancer cell division
Funder: Cancer Research UK

Abstract: While most cells in the body rely on specific signals from their extra-cellular environment to survive, grow and proliferate, metastatic cancer cells are characterised by loss of requirement for such cues. This is demonstrated by their ability to grow is soft, unstructured media like soft agar, without contact with the extra-cellular matrix. Although cell cycle regulation in anchorage-independent growth has been fairly well studied, how cancer cells are able to complete mitosis and physically divide in limited extra-cellular environments has not. We have devised a set of experiments to test the ability of cancer and non-cancer cells to divide in different artificial biochemical and mechanical environments. We will image cell division in micro-fabricated channels coated with either matrix proteins or a non-adhesive substrate, allowing us to precisely manipulate the environmental signals to which a cell is exposed during mitosis. In addition, cells will be imaged in channels of varying width to assess the effect of mechanical confinement on cell division. We have previously shown that mitotic spindle assembly requires a minimum physical space and that cells generate this space by actin-dependent mitotic rounding, an adaptation that is likely to be key for division in a high pressure tissue environment. The mitotic success of a panel of breast cell lines, from non-transformed to highly metastatic, under varying degrees of spatial constraint and with or without matrix adhesion will be assessed. In addition, non-transformed RPE1 cells that can be induced to express a single oncogene will be used to discover the how cell division behaviour is altered following oncogenic transformation. By using a biophysical, reductionist approach, we will therefore be able to carefully dissect the contribution of various biochemical and mechanical external cues on mitosis during cancer progression with a view to eventually understanding how local tissue environment affects cell division in cancer metastasis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/14/008 PIONEER A Phase I study of olaparib in combination with chemo-radiation in locally advanced pancreatic cancer
Funder: Cancer Research UK

Abstract: BACKGROUND Approximately 30% of patients with ductal adenocarcinoma of the pancreas (PDAC) present with locally advanced, un-resectable, non-metastatic disease. Capecitabine is the radiation – sensitizer of choice that is used in combined modality chemo-radiation regimens in these patients. However, most patients ultimately develop local disease progression and / or distant metastases, with a median survival of approximately 15 months. Poly (ADP-ribose) polymerases (PARP), the most abundant of which is PARP-1, have a critical role in signalling DNA single strand breaks as part of the BER pathway. PARP-1 also binds strongly to DNA double-strand breaks and has an emerging role in their repair. Preclinical data, both in vitro and in vivo, have shown that inhibition of PARP-1 will potentiate the cytotoxicity of DNA-damaging agents, including radiation. Olaparib (AZD2281) is a potent inhibitor of PARP-1 in pre-clinical and clinical (pharmacodynamic) studies, with emerging evidence of efficacy in patients with BRCA mutant malignancies, suggesting that it is a potentially active PARP inhibitor in the clinic. We hypothesise that the addition of olaparib to a capectiabine-based chemo-radiation regimen might potentiate the effects of this combined modality therapy in patients with locally advanced PDAC. AIMS The aims of this study are to explore the safety and toxicity of olaparib when administered in combination with standard capecitabine – based chemo-radiation in patients with locally advanced, inoperable PDAC, and to recommend a dose of olaparib for subsequent clinical trials. Exploratory aims will determine the PK profile of olaparib in this combination regimen, the pharmacodynamic effects of olaparib in blood and tumour (where available), and to explore anti-tumour efficacy. METHODS This will be a phase I, non-randomised, open-label, multi-centre study. Eligible patients with adequate performance status and organ function, tumour diameter of 6 cm or less, will receive standard induction chemotherapy (12 weeks of gemcitabine plus capecitabine) followed by one of escalating doses of olaparib (orally twice daily, Monday - Friday) in combination with standard capecitabine (830 mg/m2 twice daily, Monday to Friday only) in combination with radiation (50•4 Gy in 28 fractions, Monday to Friday). An additional cohort of 12 patients with “borderline” resectable PDAC will be recruited to determine the tolerability of this regimen as a "neoadjuvant" approach in this patient population. FUTURE STUDIES These results will form the basis of randomised phase II studies comparing this regimen with capecitabine-based chemo-radiation in patients with locally advanced inoperable PDAC, and (separately) in patients with "borderline" resectable disease.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: PRH/pPRH ratio as a marker of response to Cisplatin sensitivity
Funder: Cancer Research UK

Abstract: We propose a novel method to develop a predictor of resistance to platinum based chemotherapy in breast cancer, thus aiding patient selection for treatment and avoiding unnecessary cytotoxic treatment to those with platinum resistant tumours. Cisplatin is used to treat triple negative breast cancers, both Carboplatin and Cisplatin are used after first line therapy in metastatic disease. PRH transcription factor is a homeodomain protein involved in embryonic development of most major organ systems PRH phosphorylation results in loss of PRH DNA binding activity, altered sub-cellular localisation and proteolytic processing of phosphorylated PRH (pPRH) to form a truncated pPRH that can antagonise PRH activity and de-repress PRH target genes. PRH is expressed at lower levels in MCF-7 tumour cells compared to immortalised non-tumourgenic MCF10A cells, and pPRH is elevated in MCF-7 cells compared to MCF10A cells (Fig.1). This suggests that PRH may be phosphorylated and proteasomally processed in breast tumour MCF-7 cells. In MCF-7 cells in an experimentally induced further decrease in PRH levels results in markedly increased sensitivity to Cisplatin treatment and decreased p53 gene expression. MCF-7 cells are known to be relatively resistant to Cisplatin treatment but these cells become more sensitive when p53 levels are decreased or MDM2 levels are increased. Carboplatin has a similar mechanisms of action to Cisplatin. Aim: To determine whether the ratio of PRH to pPRH could be a marker of Cisplatin and Carboplatin sensitivity in primary breast tumours. Method: Breast cancer material will be sliced using a Krumdieck slicer into 250micron slices. The tumour slices will be cultured for 24 hours in the presence or absence of Cisplatin or Carboplatin and then further cultured for 48-72 hours post treatment allowing MTT viability assays to be carried out with the whole tumour slice. This will allow us to determine response of the tumour to platinum chemotherapy. Tumour slices will also be fixed in paraformaldehyde and used for immunohistochemistry with anti-PRH antibodies to assess the levels of PRH, pPRH and with antibodies against epithelial and stromal markers to assess amount of tumour tissue present. Tissue slices are amenable to assays for proliferation using BrdU incorporation and MTT assays. Outcomes could lead to translational research in developing therapeutic uses for PRH/pPRH ratio in predicting Cisplatin and Carboplatin sensitivity. With breast cancer being the second most common cancer in the world in 2002, the potential for impact is high.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Preclinical combination studies with AGC kinase inhibitor AT13148 and Bortezomib.
Funder: Cancer Research UK

Abstract: To determine whether the combination of AT13148 and Bortezomib has a synergistic, additive or antagonistic effect on ovarian cancer cell growth both in vitro and in vivo. Aim 1: Quantify the effect of the combination of AT13148 and Bortezomib on tumour cell proliferation, using the SRB assay in ovarian cancer cell lines currently available in the laboratory and the Chau and Talalay method (Adv Enzyme Regul. 1984;22:27-55) for the evaluation of synergy, additivity or antagonism. • Calu-6 • A549 • H358 • H157 Aim 2. Validate the in vitro data from Aim 1 in the in vivo setting. Specifically: Of those cell lines that show a synergistic or additive growth inhibitory effect with the combination of AT13148 and Bortezomib, two will be selected and taken forward for in vivo evaluation. There will be a maximum of 3 in vivo studies for each cell line and thus a total of 6 in vivo human tumour xenograft studies. Each in vivo study will comprise the following design: Cells will be implanted subcutaneously in vivo and tumour size monitored until a volume of approximately 100 mm3 is reached. Xenografts will be randomly assigned to one of four treatment groups: 1. Vehicle control 2. AT13148 alone (40 mg/kg, p.o. 4 days on 3 days off) 3. Bortezomib alone (1.0 mg/kg, i.p. daily) 4. Combination of AT13148 and Bortezomib as above. Treatment will then be initiated using the doses and schedules described above for up to a maximum of 21 days. Samples will be taken for pharmacodynamic analyses at the end of the study. Dose and schedule are based on in-house data for AT13148 and also on data generated by J Downward for the AT13148/Bortezomib combination.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Preclinical combination studies with MCT1 inhibitor AZD3965 and radiation
Funder: Cancer Research UK

Abstract: Treatment of human tumour cell lines and xenografts with the potent, selective MCT1 inhibitor, AZD3965 results in an increase in glycolysis and change in cellular redox status. These drug-induced metabolic changes translate into an inhibition of growth of Small Cell Lung Cancer (SCLC) xenografts in vivo. This anti-tumour effect is likely to occur as a consequence of interference with the metabolic symbiosis between the hypoxic and aerobic cells within the tumour. Such a change in metabolic status is likely to increase tumour radiosensitivity and we demonstrated that combining AZD3965 with fractionated radiotherapy to treat SCLC xenografts provided a significantly greater therapeutic effect than the use of either modality alone. The purpose of this grant is to recapitulate these results in other models of SCLC, determine an optimal schedule and extend the studies into other tumours (prostate and gastro/oesophageal) where MCT1 is known to be mediator of metabolic symbiosis.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Preclinical combination studies with AZD2014 (mTORi) and Olaparib (AZD2281)
Funder: Cancer Research UK

Abstract: Pancreatic Ductal Adenocarcinoma (PDAC) has a very poor prognosis and is an area of unmet clinical need, where new therapeutic approaches are urgently needed to improve outcome. The PI3K/Akt/mTOR pathway is frequently activated in human PDAC and in mouse models of Kras-driven pancreatic cancer. Functionally, activation of the pathway is linked to increased proliferation, survival, metabolism and therapeutic resistance. Additionally, PI3K interacts with the homologous recombination (HR) complex thereby contributing to double strand break (DSB) repair. Preclinical data from AZ Discovery Bioscience has shown gene expression analysis with certain cell lines treated with the dual mTORC1/2 inhibitor AZD8055 causing a decreased expression of a number of HR pathway genes. In addition, olaparib and AZD8055 in combination demonstrated synergistic interactions in a number of cancer cell lines. In preclinical models of breast cancer, inhibition of the PI3K pathway sensitizes tumours to PARP inhibition in both BRCA-proficient and BRCA1-deficient backgrounds, although the molecular mechanisms underlying these responses appear to vary. About 20-30% of pancreatic cancers may have “unstable” genomes, associated with somatic or germline BRCA mutations, mutations in genes involved in DNA maintenance (eg. PALB2, ATM) or genes not previously associated with DNA maintenance. These tumours tend to respond exceptionally to platinum therapy, potentially due to an underlying DDR defect (unpublished data, personal communication). Given the importance of the PI3K/mTOR pathway in pancreatic tumours, inhibiton of the PI3K-mTOR pathway along with PARP is a rational combination to evaluate. Given the paucity of data on the combined targeting of these two pathways in pancreatic cancer, we intend to evaluate the mTOR inhibitor AZD2014 in combination with the PARP inhibitor AZD2281 in pancreatic cancer cell lines in vitro in two- and three-dimensional cell cuture models, to determine its efficacy and the mechanism of action. If promising, this initial project will then be carried forward into in vivo models with the eventual goal of clinical studies.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS