NIHRDataInsights/HRCSData huggingface dataset:
Title: Molecular Phenotyping as a novel method of lymph node tracking in oesophageal cancer
Funder: Medical Research Council

Abstract: Immunohistochemistry :Bond System(Leica Microsystems, Milton Keynes,UK).Antibodies will have specificity confirmed by Western blotting with positive and negative controls. Antibodies will be optimized with positive control cell blocks and oesophageal tissue before application to primary tumours and lymph nodes. PCR for oncogenic mutations:DNA will be extracted from serial sections from formalin fixed paraffin. Select gene mutations (single nucleotide variants, SNVs) which are frequently occurring and known to be relevant to lymph node metastases from our own ongoing work and from the literature. Bioinformatics support to robustly pick deleterious SNVs and verify these within the same cases as part of the ICGC project. PCR will be performed using standard techniques and high thoroughput systems using fluidigm platforms for analysis of multiple SNVs in parallel. Cell Lines:We have a panel of cell lines derived from oesophageal adenocarcinoma including 2 lines from metastases. These have been verified either in house or as part of an international effort to verify the lines for use in in vitro model systems We will use standard sRNA methods to knockdown targets of interest or to overexpress them using standard transfection methods. Proliferation (promega Glo assay), apoptosis (FACS analysis, caspase expression) and invasion through matrigel will be determined using standard methods, already established in the laboratory for other targets. Site-directed mutagenesis may also be used to recapitulate the mutation of interest. Lymphangiogenesis: Human microvascular lymphatic endothelial cells will either be co-cultured with tumour cells or tumour conditioned medium for 24 hours. The ability of tumour cells to invade and home specifically to lymphatic vessels and lymph nodes rather than blood vessels will be determined using a combination of modified Boyden chamber and 3D co-culture models. Long-term imaging of cultures will be performed on a Leica SP5 confocal microsc


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Targeted therapy in molecular subgroups of lung cancer
Funder: Medical Research Council

Abstract: There have been some significant recent improvements in the treatment of lung cancer, in particular through targeting tumour stroma (blood vessels; through VEGFR-signalling inhibition), and tumours harbouring activating somatic mutations (EGFR and, more recently, ALK). However these advances have been largely limited to metastatic disease where the only significant role of radiotherapy is for symptom palliation. In lung cancer, the major disease settings for the therapeutic uses of radiation include (i) early disease for patients who are not candidates for surgery, (ii) locally advanced disease either alone or, more usually, in combination with chemotherapy, and (iii) treatment of isolated tumour metastases, for example in the brain. This research programme aims to use non-clinical studies to identify and prioritise new treatment options for possible clinical testing and, in particular, to identify those approaches with the greatest potential to improve radiotherapy treatment outcomes. To support this research programme, a range of model systems will be used, focused initially on non-small cell lung cancer (NSCLC). For in vitro studies, a diverse panel of NSCLC lines previously characterised for baseline gene expression and common somatic mutations has been established that broadly represents the spectrum of histologies found in NSCLC patients. This panel will be used for evaluating pharmacological and phenotypic effects within tumour cells in subsets of cell lines that represent molecularly distinct patient subsets in the clinic. A range of in vivo models will be established to determine the biological and potential clinical relevance of in vitro observations. Three biologically and clinically relevant models of lung cancer will used to support this project: models of (i) early disease (autochthonous tumours - carcinogen-induced tumours and mice genetically engineered to develop lung cancer), (ii) locally advanced disease (human tumour cells implanted as xenografts into the lung), and (iii) isolated metastases (human tumour cells implanted as xenografts into the brain). The in vitro cell lines, and in vivo models constitute an experimental platform that will be used to evaluate new targets, novel therapies and radiation combination therapies in NSCLC, and is anticipated to provide significant opportunities for collaborative studies both within the Institute and more widely. The initial focus of research is to identify novel drug targets with the potential to improve the curative potential of radiation therapy. An additional focus is to seek novel combination therapies to improve the cell killing effects of molecularly targeted therapies that are currently used in advanced disease.


Research activity codes: 5.1 PHARMACEUTICALS;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: important discovery, in collaboration with the Bartek and Halazonites labs, that the cyclin E oncogene, amongst others, produces replication stress required for ATM activation of senescence (Bartkova et al, Nature 2006: this paper is amongst the top
Funder: Medical Research Council

Abstract: Each cell in our body undergoes repetitive cycles of cell division characterized by DNA replication during S-phase, and DNA distribution to the daughter cells in M-phase. Essential for the replication of DNA are the constitutive building blocks of deoxyribonucleotides (dNTPs), which are produced by Ribonucleotide Reductase (RNR). RNR catalyzes the conversion of ribonucleotides (NTPs) to deoxyribonucleotides (dNTPs) for the synthesis of DNA during DNA replication and DNA repair. In human cells the catalytic site of RNR is formed when two RRM2 subunits are bound to two Ribonucleotide Reductase family Member 1 (RRM1) subunits. The RRM1 subunit is constantly expressed through the cell cycle. RRM2 subunit is only present during S-phase and regulated at the transcriptional and post-translational levels. We have observed that RRM2 protein is targeted by the ubiquitin proteasome system during G2-phase and M-phase of the cell cycle (D’Angiolella et al., Cell 2012). RRM2 is targeted for proteolysis by the SCFCyclin F ubiquitin ligase. Cyclin F (also known as Fbxo1) is the founding member of the E3 ligases F-box protein family and is essential for mouse development. The ubiquitin-mediated proteolysis of RRM2 by Cyclin F is required to maintain balanced levels of dNTPs during cell cycle progression. Failure to regulate dNTP levels properly causes a hyper-mutator phenotype. After genotoxic stress, RRM2 levels increase and Cyclin F is itself degraded through the activation of ATR. Such regulation allows cells to produce dNTPs for DNA repair. Accordingly, we observed that Cyclin F overexpression sensitizes cells to Ionizing Radiation (IR). Therefore, proper control of dNTP levels is required to prevent genomic instability. We will determine how ATR regulates RNR in mammalian cells. We have identified a novel substrate of Cyclin F that co-ordinates dNTP production and DNA replication. Through the study of Cyclin F-RRM2 axis we have identified novel E3s ubiquitin ligases involved in the regulation of RNR and we are currently investigating their functions. RNR is the target of many anti-cancer drugs (i.e. Gemcitabine, Hydroxyurea, Clodarabine, Triapine) used currently in the treatment of non-small cell lung cancer, pancreatic cancer, bladder cancer, and breast cancer. Inhibition of RNR is known to sensitise cancer cells to genotoxic stress. Identification of new pathways that regulate RNR and cell survival upon genotoxic stress might provide insight into drug resistance, predict response to chemotherapy, and prove to be a powerful tool for the design and implementation of new chemotherapies.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Barretts metaplasia and associated carcinogenesis
Funder: Medical Research Council

Abstract: We conduct translational research on oesophageal cancer and the precursor lesion called Barretts oesophagus. This is important because the incidence of oesophageal cancer is increasing rapidly and the outcomes are dismal. The diagnostic tools and treatments available are limited, but the MRC Cancer Medicine Unit offers a unique opportunity for beneficial research because of its proximity to the clinical environment and its opportunities for scientific collaboration. Recent achievements include development of a non-endoscopic device coupled to an immunocytological assay which has gone all the way from conception to a clinical trial. Our over-riding objective for the future is to understand the molecular and cellular drivers for the development and progression of Barretts oesophagus and in so doing to provide tools for early diagnosis, accurate prognostication and therapy which can be applied to clinical practice.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Cell Fate and Cancer
Funder: Medical Research Council

Abstract: Defining fate of stem and progenitor cells in normal, preneoplastic and malignant tissues is essential for understanding how oncogenic mutations change cell fate during carcinogenesis. By using statistical physics to analyse genetic cell fate tracking data from squamous epithelia we are able to identify simple quantitative rules of cell behaviour. This has led to the discovery of a new paradigm of adult tissue homeostasis. Normal epidermis and oesophagus are maintained by a population of progenitors with balanced stochastic fate whilst stem cells remain quiescent. In preneoplastic clones in UV exposed human epidermis, P53 mutation tilts the balance of progenitor cell fate in favour of proliferation. Stochastic progenitors are also present in primary cultures of squamous carcinoma. We are applying these quantitative insights to understand the clonal evolution of cancer in mouse models, gain molecular insight into progenitor cell fate regulation and accelerate the preclinical evaluation of candidate anticancer agents using novel assays.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Clinical trials in upper gastro-intestinal and gastric cancer
Funder: Medical Research Council

Abstract: Oesophagogastric cancers cause approximately 13,000 deaths per year in the UK, or 6% of all cancer deaths. The outlook is poor, with only 20 to 30% of patients who undergo potentially curative surgery alive 2 years later. There is therefore a great need to improve outcomes. |In patients with operable oesophageal cancer, OE02 compared surgical resection with or without two pre-operative cycles of cisplatin and fluorouracil (CF). 802 patients were randomised, making this the largest randomised trial ever conducted in this disease. The results, originally reported in 2002 (Lancet 2002, 359: 1727-1733) and updated in 2008 (J. Clin. Oncol) show that with pre-operative chemotherapy survival is prolonged and is now standard treatment in the UK. The trial attracted great interest internationally, not least because a similar, but substantially smaller American trial showed no advantage with chemotherapy. Both trials contributed to an individual patient data meta-analysis of all relevant trials and this confirmed a significant survival benefit to pre-operative chemotherapy.|Building on the success of OEO2 we are currently undertaking a randomised trial (OEO5) where patients either receive 2 cycles of CF chemotherapy followed by surgery or 4 cycles of ECX chemotherapy followed by surgery. The trial is on target to complete accrual of 842 patients in early 2011.|In patients with operable gastric cancer, the ST02 randomised trial, or MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial, compared surgical resection with or without peri-operative chemotherapy using a regimen of epirubicin and cisplatin with 5-fluorouracil by continuous infusion (3 cycles pre-operatively and 3 post-operatively.) 503 patients were randomised, and peri-operative chemotherapy was shown to significantly improve survival (HR for death 0.75 95%CI 0.6-0.93 p=0.009) with 5 year survival rates increased from 23% to 36% (N Engl J Med. 2006 Jul 6; 355(1):11-20).|Again building on this success ST03 is a phase II/III trial randomised trial where patients are randomized to 3 pre- and 3 post-operative cycles of ECX and surgery with or without bevacizumab, a monoclonal antibody against the vascular endothelial growth factor receptor. It is intended that this will be an international trial recruiting in the region of 1000 patients. Phase II recruitment is complete. |For all of these trials additional translational studies will be performed on tissue samples with the aim of identifying prognostic and predictive factors that identify patients likely to respond to these treatments.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Clinical trials in testicular cancer
Funder: Medical Research Council

Abstract: Testicular cancer is relatively rare - ~1900 new cases per annum in the UK - but is the most common malignancy in young men, and one which has doubled in incidence in the UK over the last 30 years. Diagnosed early, the chances of cure are now excellent, but the age of the typical patient means testicular cancer rates highly in terms of potential years of life lost while surviving patients will live a long time with the side effects of successful treatment. Goals for MRC CTU research into this area are therefore |(a) in the poorer prognosis patients, improving survival rates, |(b) in the good prognosis patients, minimising the impact of treatment on working status, fertility and general health in the short and long term - without compromising the high cure rates.||In December 2009 we successfully completed accrual to the first randomised trial of a novel chemotherapy regimen (CBOP/BEP) for poor prognosis metastatic germ cell tumours. The results will be available in 2010 and will inform decisions on an international strategy for these patients.|Updated results of two trials will inform the management of patients with stage I disease. In seminoma, the TE19 trial (in press, Journal of Clinical Oncology) showed that a single dose of carboplatin achieved clinically equivalent results to 2-3 weeks of radiotherapy in terms of relapse-free survival, and reduced the incidence of contralateral testis tumours. In non-seminoma, low risk patients are typically managed by post-operative surveillance, but the optimal surveillance schedule is unknown. The TE08 trial randomised patients between two different radiological surveillance schedules and updated results confirmed that stage at relapse was not compromised by carrying out less frequent CTs (presented at the NCRI conference, October 2009).|Surveillance is of increasing interest in stage I seminoma patients, 80% of whom will be cured by surgery alone. However, there is a requirement to balance the need for effective post-operative monitoring to enable prompt detection of relapse with minimising excessive exposure to ionising radiation from current scanning modalities. Current surveillance schedules are based around frequent CT scanning, which has a non-ignorable level of radiation and associated cancer risk. This could be minimised by a reduction in CT scans frequency or by a switch from CT to MRI which uses no radiation. Our randomised phase III trial (TRISST) opened in 2008 and will establish whether a reduced imaging schedule or MRI could be used as a safe and effective alternative to standard CT-based surveillance.


Research activity codes: 2.4 SURVEILLANCE AND DISTRIBUTION;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Clinical trials in lung cancer
Funder: Medical Research Council

Abstract: Lung cancer is by far the commonest cancer in the Western world, with around 35,000 new cases per year in the UK. Prognosis and treatment depend on the histological type, and the extent to which it has spread when first diagnosed. Overall, median survival is around 1 year from presentation. |Our programme is aimed at improving the results of treatment in lung cancer and establishing the best standard treatment in mesothelioma in terms of duration of survival and the quality of life. We currently have 1 open trial (QUARTZ), and 3 (LU22, MS01 and INCH) that have closed to accrual, main results have been published and further analyses are ongoing. |About a third of all patients with non small cell lung cancer (NSCLC) develop brain metastases, and once this happens median survival is around 2 months. Many of these patients will receive whole brain radiotherapy, but this has side-effects and has never been shown to extend survival or improve quality of life. The QUARTZ trial addresses this issue, and patients, all of whom will receive supportive care with dexamethasone, are randomised to either receive whole brain radiotherapy or not. The primary outcome is Quality Adjusted Life Years so as to combine duration and quality of life. We are aiming to accrue around 500 patients to this challenging trial, and the results will potentially have a major impact worldwide.|In patients with surgically resectable NSCLC, our aims are to see if we can improve survival by giving pre-operative chemotherapy. LU22 closed in July 2005 with 519 patients, the largest trial of neoadjuvant chemotherapy in non-small cell lung cancer. The main results were presented in the Lancet in 2007. The data is currently contributing to an MRC CTU led individual patient meta-analysis on this subject. |The MS01 trial investigated the value of chemotherapy for patients with mesothelioma. It opened in 2001, following a feasibility study to see if patients would accept a randomisation to supportive care alone. The trial closed in July 2006 with 409 patients, making it the second ever largest trial in this disease. The results were published in the Lancet in June 2008, and a further paper, looking at quality of life is underway. |INCH evaluated CHART radiotherapy with or without chemotherapy, the trial closed early due to poor accrual due to the few number of centres in the UK that were able to offer CHART.


Research activity codes: 6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Clinical trials in gynaecological cancer
Funder: Medical Research Council

Abstract: Epithelial ovarian carcinoma (EOC) is the fourth most common cause of cancer-related death in women and the most lethal gynaecological malignancy. Although it responds well to initial chemotherapy (response rates > 70%) the majority of women (even those who achieve a complete remission) ultimately develop recurrent disease and die. Median progression free survival (PFS) for patients with advanced disease ranges between 16 and 21 months while the median overall survival (OS) lies between 31 and 57 months.||Early treatment of relapse based on the blood biomarker CA125 was evaluated in the OV05 trial. First results, presented at the ASCO in 2009 suggested that starting chemotherapy early based on CA125 alone compared to waiting to start chemotherapy when symptoms occur, does not improve overall survival or quality of life. A manuscript for publication is currently under review.||New treatment strategies based on the fact that ovarian tumours are associated with high expression of angiogenic factors including vascular endothelial growth factor (VEGF) and endothelial growth factor (EGF) have been developed. These factors are targets for newer drugs which block growth factors or their receptors including bevacizumab (ICON7), erltotinib (OV07) and cediranib (ICON6). First results of ICON7 will be presented in 2010. The standard treatment of newly diagnosed ovarian carcinoma includes primary surgery with removal of as much of the tumour as possible (optimal debulking) followed by platinum-based chemotherapy. Some chemotherapy before and after surgery (neoadjuvant chemotherapy) is an alternative treatment strategy being investigated in the CHORUS trial. Optimal debulking may be easier to achieve after 3 cycles of chemotherapy and reduced post operative morbidity could improve quality of life. |Giving standard chemotherapy with carboplatin and paclitaxel as weekly treatments rather than 3 weekly may lead to improved progression free and overall survival in women with newly diagnosed ovarian cancer. This will be investigated in the recently funded ICON8 trial.||ICON3 results, published in 2001 were controversial. OS and PFS were no better in patients treated with platinum based chemotherapy plus paclitaxel than in patients treated with platinum based chemotherapy alone. The ICON3 p53 study investigates the role of the p53 gene in response to platinum. There is evidence to support the hypothesis that patients with wild type p53 have high response rates to single agent carboplatin and may gain no benefit from the addition of paclitaxel chemotherapy. This may explain the result of ICON3 and ICON4. Results will be available in 2011.


Research activity codes: 6.4 SURGERY;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS