NIHRDataInsights/HRCSData huggingface dataset:
Title: Control of cell death during mitosis and in response to anti-mitotic drugs.
Funder: Cancer Research UK

Abstract: The development of cancer is characterised by the loss of controls over cell cycle progression and resistance to cell death. Much has been learned about the control of these fundamental processes, but the interactions between them are still not understood. In particular, it is not known how cell survival is controlled during mitosis. Defects in mitosis and a subsequent failure to initiate apoptosis can result in the propagation of chromosome aneuploidy, a characteristic feature of many cancer cells. Most importantly, the relationship between mitotic controls and cell death is critical for responses to anti-cancer drugs such as taxol (paclitaxel), vinca alkaloids and a new generation of enzyme inhibitors that target mitotic cells. However, because we do not fully understand the cellular responses to these drugs, in particular how they can induce cell death, we cannot yet optimise the use of existing drugs, reduce the severe toxic side effects and design the most effective trials for new reagents.<br/><br/> Recently, my group has made significant progress in understanding the mechanisms controlling cell death by apoptosis during mitosis and in the mitotic arrest induced by drugs such as taxol. We now wish to bring together our efforts in a coordinated programme of research to determine the molecular mechanisms underlying the control of cell survival during cell division and in response to anti-mitotic drugs in order to provide basic information that will facilitate a better understand mechanisms of cancer development and resistance to anti-cancer drugs, and to engender novel strategies for the selective killing of cancer cells.<br/> <br/>Our strategy is to use a range of approaches in biochemistry and cell biology to identify and characterise the key proteins involved in the control of cell death during mitosis and mitotic arrest, and to understand the temporal control of these processes within cells. Control of processes during cell division is mainly at the post-transcriptional level and we will focus on two major interacting mechanisms that control proteins during this period of the cell cycle, namely protein phosphorylation and ubiquitin-mediated proteolysis. We intend to use the basic knowledge that we derive from these approaches to test the functions of specific proteins and their modifications in the responses to anti-cancer drugs in human cancer cells. Our goal will be to provide a scientific basis to design improved strategies for patient treatment.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Towards personalised cancer care: circulating nucleic acids for early detection and monitoring of breast cancer
Funder: Cancer Research UK

Abstract: Background: Molecular characterization of circulating free DNA (cfDNA) and tumour cells (CTCs) is proposed as a potentially powerful tool to aid cancer diagnosis and determine individual therapies. Results of our recent BIDD funded study, which surveyed the whole genome in cfDNA and paired tumour of 65 breast cancer patients using Affymetrix® SNP 6.0 arrays, suggested the clinical importance of cfDNA analysis. We were able to distinguish between patients with primary breast cancer and healthy controls and between pre-operative breast cancer patients and patients on follow-up after surgery and treatment. In patients on follow-up, up to 10 years after diagnosis, patients had DNA in plasma with specific copy number variations (CNVs) that mirrored those in their primary cancer, despite the fact that they had no clinically-evident recurrent disease. Several CNVs were more common in node positive than node negative patients and may therefore be helpful in deciding on therapeutic management. Recent blood-based profiling studies of microRNAs suggest that these also hold potential as novel non-invasive biomarkers. The CellSearch system is used to measure CTCs in patients with metastatic cancer, but few CTCs are intermittently present in patients after primary treatment. New filter capture methods have the potential to enrich larger numbers of CTCs, amenable to molecular analysis and will be compared with cfDNA in this programme. _x000D_ _x000D_ Aims: To develop and validate a panel of circulating markers (cfDNA, miRNA and CTCs) and demonstrate that a circulating phenotype is an important prognostic and predictive factor for relevant clinical outcomes in breast cancer._x000D_ _x000D_ Methods: We will use a combination of SNP array, miRNA Array, bioinformatics, quantitative PCR and statistical modelling to develop and validate a panel of cfDNA and miRNA markers and compare their sensitivity and specificity in plasma and CTCs, enriched using a filter capture technique. We will carry out prospective studies with our candidate markers to determine whether blood screening can be offered as 1) an early diagnostic test for use in comparison with breast screening and 2) to predict relapse. _x000D_ _x000D_ How the results of this research will be used: This research may ultimately lead to increased survival of patients, due to earlier detection, and may aid in stratifying patients at risk to targeted therapies and in monitoring therapeutic efficacy.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Quantifying the relationship between cancer cell genotype and phenotype. Determination and validation of the gene expression changes that drive the specific morphological changes essential for breast cancer metastasis.
Funder: Cancer Research UK

Abstract: Background_x000D_ Despite the vast amount of data that have been generated in recent years on cancer cell genotypes, a significant challenge in the post-genomic era will be to understand how genomic alterations drive cellular phenotypes, such as the dramatic changes in morphogenesis that occur during metastasis. _x000D_ We have previously developed technologies to quantify the morphology of single cells and cell populations to precisely investigate changes in cell shape. We are currently using these methods to quantify the morphology of a panel of breast cancer lines in 2D and 3D culture. Using these methods, we can also quantify hetereogeneity and identify morphologically distinct subpoluations within in isogenic cell lines. _x000D_ Genome-wide mRNA expression levels and genomic copy number variations have been determined for all the lines we are investigating by a laboratory at the ICR/Breakthrough Breast Cancer Center. This allows us to perform statistical analysis to find patterns of gene expression that relate to quantifiable differences in cell shape. In addition, we are working in collaboration with The Cancer Genome Atlas Project to profile the genotypes and morphological phenotypes parallel following treatment with different small molecules. In this project, we aim to determine how genotypic alterations are linked to specific changes in morphological in cancer cells. _x000D_ Aims_x000D_ (1) To classify a panel of 20-40 breast cancer cell lines based on morphology and identify patterns of gene expression that are correlated with and/or control cell shape._x000D_ (2) To perform quantitative morphometric analysis of cell invasion in 3D matrices._x000D_ (3) To determine the whether highly invasive cells represent stable subpopulations within tumour cell lines._x000D_ _x000D_ Methods_x000D_ In order to complete these studies we will use:_x000D_ - Automated high-throughput image acquisition and feature analysis of single cells in both 2D and 3D. Th laboratory is equipped with two Opera microscopes, each capable of capturing over 100,000 unique images per day._x000D_ - High-throughput analysis of 3D morphology._x000D_ - Machine-learning methods to quantify and classify independent phenotypes. The ICR has recently acquired an Altix UV computer in order to facilitate this work._x000D_ - Statistical analysis to determine correlations between gene expression, copy number and morphological features._x000D_ - RNAi and small-molecule perturbation._x000D_ _x000D_ _x000D_ The results of this work will be primarily used to identify and validate genes whose changes in expression are causal to the morphogenesis of metastatic cells._x000D_


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CRUKD/11/012: ROCOCO: A phase I dose escalation trial of Radiotherapy and Olaparib (a PARP1 inhibitor), in combination for carcinoma of the oesophagus
Funder: Cancer Research UK

Abstract: Background There is a need for more effective treatment with acceptable toxicity for patients unsuitable for chemoradiotherapy as radiotherapy alone is not curative in oesophageal cancer. In this trial we will evaluate the combination of radiotherapy with the PARP inhibitor Olaparib, which offers tumourspecific radiosensitisation and potentially an excellent toxicity profile. Aims 1) Define the tolerability, MTD and DLT of Olaparib in combination with radiotherapy for oesophageal cancer 2) Define a dose suitable for phase II evaluation 3) Gather information on soluble and skin biomarkers to guide their use in phase II testing Summary Patients with localised oesophageal cancer unsuitable for surgery or platinum containing concurrent chemoradiotherapy (CRT) will be treated with l radiotherapy to a conformal CT-planned volume at a dose of 60Gy in 30 daily fractions (treating 5 days per week from Monday-Friday). All patients except those on the standard care arm will have Olaparib from day -3 (relative to the start of radiotherapy) up to day 40 (i.e. continuing for 7 days per week throughout radiotherapy). Cohorts: Olaparib – 100mg od, 100mg bd, 200mg bd, 300mg bd and standard care (no Olaparib). 3 months post completion of radiotherapy patients will receive a triphasic CT scan and endoscopy with biopsy to assess response. Patients will attend out-patient clinics for regular follow-up appointments in accordance with the protocol schedule. Blood samples and skin biopsies will be taken at specific timepoints in accordance with the protocol schedule for translational/pharmacodynamic purposes . Tissue samples from diagnostic biopsy and the biopsy taken at 3 months for response assessment will also be retained for possible translational work.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Investigating telomere instability and fusion in human cells
Funder: Cancer Research UK

Abstract: BACKGROUND:_x000D_ This proposal is a continuation of work developed during a CRUK funded fellowship, during which_x000D_ time we examined telomere dynamics, dysfunction and fusion in human cells in vitro, and translated_x000D_ this information to primary normal and diseased tissues ex vivo._x000D_ We provided the first direct evidence of telomere erosion, dysfunction and fusion during tumour_x000D_ progression in humans; we believe that this mechanism drives large scale genomic instability and is_x000D_ applicable to numerous tumour types, both haematological and solid. As well as providing_x000D_ mechanistic insights into disease progression, these data indicate that high resolution telomere_x000D_ length and fusion analysis can provide important prognostic information. We provided a definition of_x000D_ the length at which telomeres undergo fusion, and insights into the DNA repair processes that_x000D_ operate at short telomeres. Furthermore our data indicate that chromatin structure is important in_x000D_ conferring telomere stability, and that cancer stem cells exhibit a distinct telomere chromatin_x000D_ conformation that when perturbed causes a striking telomere instability phenotype._x000D_ AIMS &OBJECTIVES:_x000D_ We wish to follow up this work by focusing on two key questions_x000D_ - What role does chromatin structure play in conferring telomere stability, telomere length_x000D_ determination and is this differentially regulated in cancer stem cells?_x000D_ - What processes drive telomere fusion and what are the resulting mutational events?_x000D_ METHODS:_x000D_ Working with human cancer cells, including putative cancer stem cells, we will use our singlemolecule_x000D_ assays to screen a panel of genes implicated in chromatin biology, for changes in telomere_x000D_ stability, telomere length and telomere fusion frequencies. We will use N-ChIP to examine changes in_x000D_ chromatin structure in the context of telomere instability and length differentials. We will examine_x000D_ telomere fusion and mutation by testing key protein components and small inhibitors involved in_x000D_ double-strand break repair, and by developing genome-wide approaches to characterise the full_x000D_ spectrum of mutation that accompanies telomere fusion._x000D_ HOW THE RESULTS OF THIS RESEARCH WILL BE USED:_x000D_ This project will investigate the biology of telomere instability and fusion, a key mutational_x000D_ mechanism that can drive tumour progression. In doing so this work may provide therapeutic targets_x000D_ that could allow specific targeting of the telomere biology of cancer cells and/or cancer stem cells._x000D_ Understanding the process of telomere fusion may provide an opportunity for intervention in the early_x000D_ stages of the neoplastic progression. We also anticipate that the development of more sensitive_x000D_ methods to detect telomere dysfunction may provide more diagnostic/prognostic tools.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: MRE11 as an Outcome Prediction Biomarker in Bladder Cancer Radiotherapy (MOBIBLART)
Funder: Cancer Research UK

Abstract: Background Muscle invasive bladder cancer carries a 50-60% cause-specific survival at three years (3-yr CSS) with radical treatment, either by surgery (cystectomy) or radiotherapy, with neo-adjuvant cisplatin-based chemotherapy given to fit patients. No randomised comparison has successfully been made, so treatment is based on patient choice with recommendations from their urologist and oncologist. There is an unmet clinical need to develop a test that predicts a patient’s likely benefit from radiotherapy, in order to rationalise the management of muscle invasive bladder cancer. In an 86 patient test cohort and 93 patient validation cohort, we have shown that pre-treatment immunohistochemical (IHC) expression of the DNA damage signalling protein MRE11 in bladder tumours was predictive of outcome following radiotherapy (43% vs 70% 3-yr CSS for low and high expressers, respectively) but not cystectomy. We now need to develop the assay to appropriate standards (final stage of biomarker discovery and assay development phase) and to define the relationship of the biomarker to clinical outcome in a prospective analysis of retrospective tissue collections (first stage of biomarker qualification phase). Aims 1. to further develop the MRE11 IHC assay for use as a prospective predictive biomarker of radiotherapy outcome, 2. to validate our finding in a prospective analysis of retrospective tissue collections from two recent phase III clinical trials of bladder radiotherapy (BCON and BC2001), and 3. to progress the assay further by developing a multivariate nomogram, using MRE11 as a continuous variable and including known prognostic factors. Methods We have 250 samples from the BCON trial and will have 340 samples from the BC2001 trial in year 2. The study will take place in GCP-standard and NHS pathology laboratories in multiple centres (Oxford, Manchester, Leeds and Birmingham). After the development of an appropriate testing algorithm, trial slides will be cut and stained on automated IHC machines, with appropriate control slides distributed to each centre, and scored by clinical pathologists. Data will be analysed as before using the lower quartile versus the remainder, but we shall also develop a multivariate nomogram, which would give a percentage cure rate in individual cases, thus facilitating patient decision-making. How the results of this research will be used If the assay development is successful, we plan to test the assay prospectively in a randomised controlled clinical trial, where patients are randomised to counselling for radiotherapy versus surgery with or without knowledge of their MRE11 IHC result.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Lymphoma and myeloma: Understanding the patient pathway and promoting early diagnosis
Funder: Cancer Research UK

Abstract: Background There is a dearth of information about the pathway (symptom onset to diagnosis) in patients with lymphoma and myeloma, particularly in terms of clinical signs, symptoms, help-seeking, GP management, decision-making, referral pathways and time-to-diagnosis. Patients with these haematological malignancies are, however, more likely to present as emergencies and less likely to be referred via the two-week rule than those with other cancers. They are also less likely to be referred directly to haematology and may experience prolonged diagnostic delay. The effect of this on outcome has never been systematically examined. Aims We aim to reduce time-to-diagnosis in patients with lymphoma and myeloma. Specific aims are to: 1. Examine the primary and secondary care pathways and the: a) primary care attendance patterns and symptom profiles prior to final diagnosis b) duration of time between significant events (symptom onset, help-seeking, hospital referral(s) and final diagnosis) and their impact on outcome c) potential impact of socio-demographic factors, together with stage at presentation, on a) and b) 2. Conduct an in-depth study examining help-seeking behaviour Methods We plan a two-part project embedded within the Haematological Malignancy Research Network (HMRN) infrastructure. HMRN is a unique population-based registry of haematological malignancies sited across two Cancer Networks. It will provide a cost-effective cohort of myeloma and lymphoma patients diagnosed in 2012 (1000 new diagnoses annually). A significant amount of information will be available for these patients from HMRN core data-collection. This will be supplemented by additional information collected as part of the proposed study, which will include: 1. Data on the patient pathway from primary and secondary medical records (first help-seeking, symptoms, GP visits, hospital referrals and appointments and time between each of these events). 2. Qualitative data from in-depth patient interviews How the results of this research will be used This will be the largest, most comprehensive study examining the entire patient-pathway of these cancers. Findings will enable us to develop a clear understanding of the pathway and identify potential interventions to reduce time-to-diagnosis. Findings could also be used to develop: • computer-based decision support systems to enable GPs to identify patients with these cancers, thereby promoting appropriate investigation and referral, reducing time-to-diagnosis and improving outcome(s) • educational resources to promote help-seeking for these cancers Findings will be disseminated locally, nationally, and internationally by the applicants via peer-reviewed publications, conferences, the HMRN website (www.hmrn.org) and our patient newsletter.


Research activity codes: 4.3 INFLUENCES AND IMPACT;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: CANCER AND NEOPLASMS
Title: Molecular mechanisms underlying the control of ribosome biogenesis
Funder: Cancer Research UK

Abstract: Background: the production of ribosomes is crucial for cell growth and division, and is therefore especially important in rapidly-dividing cancer cells. Ribosome biogenesis is a complex process, involving the production and processing of four rRNAs and more than 80 different ribosomal proteins (RPs), and their correct assembly into mature ribosomes. Most of these steps occur in nuclear regions termed nucleoli which are known to be altered in cancer cells. A variety of anti-cancer agents interfere with ribosome production. The mammalian target of rapamycin, mTOR, regulates the production and processing of rRNAs and the synthesis of RPs. However, it is not known how mTORC1 does this. The mRNAs for RPs are regulated through sequences termed 5’-TOPs (5’-tracts of pyrimidines). Importantly, recent data indicate that many more mRNAs, encoding proteins involved in cellular metabolism, ribosome production and other processes, may also be regulated in a similar way. mTORC1 signalling is activated in many cancer cells and is an established target for anti-cancer therapy._x000D_ _x000D_ Aims: (i) to study the control of translation of recently-identified novel 5’-TOP mRNAs, in particular ones encoding proteins involved in ribosome production and anabolic metabolism; (ii) to explore the mechanisms by which mTORC1 controls translation of 5’-TOP mRNAs; (iii) to investigate how mTORC1 signalling controls rRNA processing, in particular BOP1, a protein involved in this process which we have shown is regulated by mTORC1; (iv) to explore the control of the pentose phosphate pathway (PPP; which generates precursors for RNA production) and its links to mTORC1._x000D_ _x000D_ Methods: we will use a range of established approaches plus recently developed methods including ones developed in our own laboratory. These include sucrose density gradient centrifugation together with Northern blotting and qPCR to study the translational control of established and novel 5’-TOP mRNAs; a novel RNA tagging method in combination to stable isotope labelling of cells in culture (SILAC) to identify mTORC1-regulated proteins that bind 5’-TOP mRNAs; phosphoproteomic and other methods to study the control of rRNA-processing components by mTORC1; Northern blotting to investigate the control of rRNA processing; siRNA and other approaches to study the control of the PPP and its links to mTORC1 and ribosome biogenesis including a novel non-radioactive approach to studying rRNA transcription and turnover._x000D_ _x000D_ How the results will be used: the findings will help define how ribosome production is controlled by oncogenic signalling pathways and identify novel regulatory components which may provide targets for developing new anti-cancer drugs._x000D_


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS