NIHRDataInsights/HRCSData huggingface dataset:
Title: TOR signalling and control of mitotic commitment
Funder: Cancer Research UK

Abstract: A tight link between cell growth and cell cycle progression allows eukaryotic cells to divide at a constant size during continuous proliferation and produce organisms of particular sizes. TOR kinase pathways modulate this link in response to environmental cues that include stresses and nutritional availability. As cancer is a disease of uncontrolled proliferation and cancer cells inappropriately colonise parts of the body, they are invariably more stressed than normal tissues. Therefore changes in TOR signalling are found in cancers and components upstream and downstream of the mTOR kinase are often altered in tumours. Rapamycin, a specific TOR kinase inhibitor, blocks proliferation, prompting clinical trials to test rapamycinÆs potential as a cancer therapeutic. A better understanding of TOR signalling would further refine such trials and unveil the potential for multi-agent therapies. The complexity of signalling pathways in mammals makes such efforts a major challenge. In contrast the simplicity of a single celled lifestyle and strong genetics make yeasts ideal model systems This project will extend our understanding of the principals of TOR signalling by exploiting our recent observation: a key role for the TOR pathway in coordinating cell size at mitosis with environmental settings. The exact molecular mechanisms by which TOR signalling is regulated to control mitotic commitment remains to be established. Our key objectives are: 1: better general understanding of the regulation of TOR complexes and kinases in the signalling pathway in response to changes in the environment. And 2: to isolate and characterise mutants of the TOR pathway that are specifically defective in nutrient stress induced acceleration of mitosis. In shedding light on the mechanisms behind TOR pathway control of MAP kinase activation and mitotic onset, this work will set the scene to exploit growth and cell cycle controls for targeting of human cancer cells proliferating in alien environment and aim to allow clinicians a more specific control of TOR inhibition to prevent unwanted MAPK activation that promote mitosis.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Cellular responses to DNA damage
Funder: Cancer Research UK

Abstract: Background: The prime objective for every life-form is to deliver its genetic material, intact, to the next_x000D_ generation. This must be achieved despite DNA being constantly attacked by endogenous and_x000D_ environmental agents. To counter this threat, life has evolved systems – sometimes collectively termed_x000D_ the DNA-damage response (DDR) – to detect DNA damage, signal its presence and mediate its repair._x000D_ Despite major advances in our understanding of DDR-processes, much remains to be learned._x000D_ Relevance to cancer: Research into the DDR is arguably of greater relevance to cancer than any other_x000D_ area of research. First, most agents known to cause cancer do so by generating DNA damage and_x000D_ ensuing mutations. Second, most inherited cancer-predisposition syndromes are caused by underlying_x000D_ DDR defects. Third, surgery aside, by far the most widely used – and effective – cancer treatments_x000D_ involve DNA-damage generation by radiation or chemicals. Success of such treatments reflects the_x000D_ DNA damage killing cancer cells, while therapy-failure arises when cancer cells survive by mediating_x000D_ DNA-damage repair. Furthermore, the side-effects of such treatments are caused by DNA damage to_x000D_ normal tissues. Fourth, DDR-markers have potential utility in cancer diagnosis, cancer prognosis and_x000D_ cancer-stratification to allow individualized tailoring of therapies. Finally, there is a growing realization_x000D_ that inhibitors of certain DDR enzymes have anti-cancer potential, either as stand-alone agents or in_x000D_ combination with existing therapies._x000D_ Specific aims of research: The goals of our research are to: identify important DDR-proteins,_x000D_ particularly those responding to DNA double-strand breaks (DSBs); provide mechanistic insights into_x000D_ how these proteins function; determine how DDR events are affected by chromatin structure; and_x000D_ understand how the DDR impinges on diverse cellular events. It is our hope that, together with the work_x000D_ of others, such research will indicate how DDR dysfunction can lead to human disease and how such_x000D_ diseases might be better diagnosed and treated._x000D_ Outline of research plan: We will use molecular-biology, biochemical, cell-biology and moleculargenetics_x000D_ approaches to investigate DDR events, particularly those triggered by DSBs. Thus, we will_x000D_ investigate how phosphorylation, acetylation, ubiquitylation and sumoylation affect the functions of_x000D_ certain DDR proteins; we will explore how and why the DDR triggers changes in chromatin structure; we_x000D_ will investigate how chromatin structure impinges on the DDR; we will explore how the DDR affects_x000D_ transcription and potentially RNA processing; and we will use bioinformatics-based, biochemical and_x000D_ functional-screening methods to identify additional proteins that function in, or impinge upon, DDR_x000D_ processes.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: CANCER AND NEOPLASMS
Title: The adenomatous polyposis protein in colorectal cancer: from biochemistry to tissue architecture
Funder: Cancer Research UK

Abstract: Colorectal cancer is the second most common cause of cancer deaths in the Western world. The earliest molecular change in most sporadic colorectal cancers is mutation of the Adenomatous polyposis coli (Apc) gene and such mutations are responsible for familial adenomatous polyposis (FAP), a familial form of colorectal cancer. Apc controls the activation of a transcriptional program that maintains cells in a less differentiated, more proliferative state. This involves the stabilisation of beta-catenin, a protein that supports the function of adhesion proteins and regulates the activity of transcription factors. Apc is a scaffold for the protein complex that mediates the phosphorylation of beta-catenin, which targets it for proteasomal degradation. This complex is controlled by Wnt signalling. Apc also interacts with cytoskeletal proteins and their regulators. These interactions contribute directly to cell migration and adhesion, but also cell division and possibly apoptosis. Mutations in Apc lead to the stabilisation of beta-catenin, which causes cells to continue proliferating and maintains them in less differentiated state. In this context, loss of non-beta-catenin related functions of Apc, which cause genetic instability, decreased cell migration and diminished apoptosis, become particularly relevant because they confer a significant advantage to cells. To understand the contribution of individual functions of Apc to tumourigenesis, we will use experimental approaches that span different levels of resolution. This includes visualising changes in gut tissue architecture induced by Apc loss in four dimensions, measuring contribution of specific Apc functions in cultured cells, and elucidating biochemical properties of the Apc molecule and its protein interactions. Specifically we will: Aim 1: identify pre-malignant changes in gut tissue that result from changes in Apc using quantitative parameters to describe tissue architecture in normal and Apc mutant tissue in four dimensions; Aim 2: determine how mutations in Apc affect cells in interphase and mitosis; Aim 3: establish a hierarchy of interactions to identify different Apc-containing protein complexes to understand the regulation of the Apc molecule. Results form this program will greatly enhance our understanding of gut physiology and provide insights into the link between molecular changes and tissue changes during early tumourigenesis. The establishment of screening programs throughout the UK has led to the detection of tumours at earlier stages making identifying prognostic markers and therapeutic targets increasingly important. Results from our proposed program will identify markers that could facilitate prognosis and treatment of colorectal cancer. Last updated 21/07/2010


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: CR-UK Children's Cancer and Leukaemia Group (CCLG) Trials Unit
Funder: Cancer Research UK

Abstract: The Cancer Research UK Clinical Trials Unit's (CRCTU) mission for the CRUK CCLG CTU will be to establish a leading academic unit for clinical trials in childhood cancer and leukaemia. CRCTU is one of the largest cancer trials units in the UK and a member of the Birmingham Centre for Clinical Trials. The CRCTU is also an integral part of the Birmingham Experimental Cancer Medicine Centre and the Birmingham Cancer Research UK Cancer Centre. The unit receives core funding from Cancer Research UK.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);5.9 RESOURCES AND INFRASTRUCTURE (TREATMENT DEVELOPMENT)
Health categories: CANCER AND NEOPLASMS
Title: The Golestan Cohort Study follow-up: An investigation of environmental and genetic risk factors for oesophageal cancer in north-east Iran
Funder: Cancer Research UK

Abstract: To identify risk factors for esophageal cancer by a comprehensive assessment of environment, lifestyle and genetics in a large cohort of men and women living in a high incidence area of Iran. Golestan Province, in north-east Iran, is a semi-desert area with a very high incidence of esophageal cancer. The Golestan Cohort Study was started in 2005, partly funded by a project grant from Cancer Research UK in order to: i) identify risk factors for EC (ii) establish a biospecimen bank for blood, urine, hair, and nail samples to be used in molecular and genetic studies of cross-sectional or nested case-control design. (iii) provide a model for population-based studies in a country in economic and social transition based on collaboration between local health workers, local health authorities, national research centers, national government, and international research institutions. Over 50,000 men and women from both urban and rural communities in Golestan province enrolled in the cohort and have had a comprehensive assessment of ethnicity, occupational history, socioeconomic status, past medical history, family history of cancers, gastrointestinal symptoms and signs, tobacco, opium and alcohol use, oral health, anthropometric characteristics, physical activity, and tea drinking habits, including tea temperature. Nutritional patterns have also been evaluated using a food frequency questionnaire (FFQ) specifically developed for this population and validated during the pilot study. The FFQ covers 116 food items, including bread and cereals, meat and dairy products, oils, sweets, legumes, vegetables, fruits, and condiments, as well as cooking methods. The follow-up phase of the cohort has now begun and funding is sought for the next five years. We aim to contact all participants at least once a year to obtain detailed information about incident cancers and to collect tumour material for molecular studies. Last updated 21/07/2010


Research activity codes: 2.6 RESOURCES AND INFRASTRUCTURE (AETIOLOGY);2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development of vaccination strategies to enhance tumour specific T cell response
Funder: Cancer Research UK

Abstract: 1. Background to the proposal. T cell responses to natural infection are orders of magnitude greater than those observed in cancer patients in response to current vaccination protocols. It is most likely, therefore, that optimizing tumour vaccination protocols will require a deeper understanding of the signals that the immune system coordinates in order to respond to pathogenic infection. 2. Relevance to Cancer. Compounds that mimic these signals and that can enhance the interplay between innate and adaptive immune response may therefore be exploited as adjuvants in current tumour vaccination strategies. 3. Specific aims of the research. The overall aim of this research programme is to build up a detailed picture of the mechanisms controlling the cellular immune response to tumour specific proteins and to develop vaccination strategies to enhance tumour specific T cell responses by bridging the adaptive and innate immune response. 4. Outline plan of research. Research will be divided into two complementing programmes: the first part will be focused on the analysis of the role of invariant NKT cells in assisting priming of antigen specific T and B cell responses, while the second part will focus on the analysis of T cell responses specific to the tumour specific antigen NY-ESO-1 and strategies to enhance NY-ESO-1 specific responses. Last updated 21/07/2010


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Development of radio-immunotherapy combinations in cancer
Funder: Cancer Research UK

Abstract: The research aims of the Targeted Therapy Group are to define the optimal ways to combine radiotherapy (RT) with immunotherapy in the treatment of cancer and to apply what we learn from the experimental programme to improving outcome in clinical trials. RT remains one of the most important treatment modalities for cancer, with over 50% of all cancer patients receiving RT at some stage in their treatment and approximately 40% of all patients that are cured of their malignancy receiving RT. However, many patients treated with RT relapse locally or systemically after treatment and therefore new approaches to enhance the efficacy of RT are required to improve outcome for cancer patients. The research areas covered by the programme include investigating and developing radioimmunotherapy (RIT) or targeted radiation and combining external beam radiation therapy (EBRT) with immunotherapy. The specific aims of the research in RIT are to increase our understanding of the mechanisms of action of RIT in order to inform and optimise the clinical application. These include investigating the relative contributions of targeted radiation and monoclonal antibody (mAb) effector functions to the induction of tumour cell death. This work builds from in vitro studies investigating the molecular mechanisms of combined mAb and RT induced cell death to in vivo studies of RIT that allow us to investigate using clinical relevant reagents such as anti-CD20 mAb. Another aspect of the research programme focuses on how tumour cell death induced by either local RT or systemically delivered targeted radiation can act to alert the host immune system and promote anti-tumour activity. We are specifically interested in investigating the roles played by the key host immune effector cells involved in the initial innate and subsequent adaptive immune response to the clearance of dying tumour, focusing on the macrophage and dendritic cell antigen presenting cell (APC) populations. This will be achieved by using depletion model systems that allow us to manipulate key APC populations and by applying novel immunostimulatory mAb to augment immune effector responses against tumour. We are also interested in determining the potential role played by myeloid derived suppressor cells (MDSC) in the regrowth of tumours after receiving RT and the effects of therapeutic Inhibition of CD11b+ myelomonocytic cells on local RT tumour control. In summary our research aims to further define the factors which are important in combining RT with immunotherapy and to translate these findings to early phase clinical trials. Last updated 21/07/2010


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES;5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/05/002: Trans-BILCAP: Assembling a tissue collection from patients in the BILCAP trial
Funder: Cancer Research UK

Abstract: Background: Cancer of the bile duct and gallbladder (biliary tract cancer) is less common than many abdominal malignancies and as a consequence poorly studied. The BILCAP trial seeks to identify whether giving chemotherapy with capecitabine after potentially curative resectional surgery reduces the very high relapse rate. Relevance to cancer: Compared to colorectal and other gastrointestinal cancers there is little information linking biomarkers to tumour staging, aggression, prognosis or response to chemotherapy. This is because no substantial tissue collection with linked clinicopathological data has existed to facilitate such studies. Specific aims of the research: We plan to obtain formalin fixed paraffin embedded specimens of biliary tract cancer and blood for DNA in the context of the BILCAP trial. Outline plan of research: With the resource of around 350 specimens we will be able to: 1. Relate tissue biomarkers to the tumour stage and other conventional histological marker related to tumour aggression at presentation 2. Relate biomarkers to clinical progression 3. Relate biomarkers to response to chemotherapy For all samples TMAs will be produced and tumour and normal DNA extracted. If feasible RNA will be extracted with sufficient quality to allow expression studies. This ultimately may be useful in diagnosis, prognosis, monitoring response to therapy and identifying recurrence. Outline. This is a category 3 TRICC grant application for sample collection only. In co-operation between the CRUK Birmingham and Southampton Cancer Trials Units and the Southampton ECMC tissue blocks and blood will be obtained and stored in Southampton for future use. A specific analysis programme will be submitted within 2 years of grant activation. It is anticipated that the material will be "open access" in the future


Research activity codes: 4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS
Title: Clinical and Molecular Pharmacology of Novel Anticancer Agents and their Delivery
Funder: Cancer Research UK

Abstract: Background & relevance to cancer: Therapeutic viruses can be deployed as versatile anti-cancer drugs that have the unique ability of selective amplification within tumours. Exploiting mutations, pathway defects and the immune suppressed environment, these 'oncolytic' viruses show good activity in fully transformed cells with few side effects. They also promise synergy with conventional treatment modalities. However, clinical experience with first generation agents has been largely disappointing with significant efficacy only seen when virus particles have been injected directly into tumour nodules. This is largely a result of poor biodistribution kinetics of virus particles in human patients, preventing sufficient infection of target tissues. A lack of pre-clinical model systems that accurately predict human host - vector interactions is one of the major factors frustrating translation of virus based therapeutics from the laboratory to the clinic. Programme aims: Building on our recent progress, this programme seeks to further improve our understanding of factors that restrict the success of oncolytic viruses and develop strategies to overcome them. Using a combination of genetic and chemical engineering we aim to enable successful and repeat intravenous application of 'virotherapy' to treat advanced disseminated cancer. Our approach to this problem will be to interrogate our hypotheses in advanced pre-clinical models and human samples where appropriate. Outline Plan: The program is divided into 3 areas of investigation and drug development: 1) Improve of drug pharmacokinetics by increasing plasma half-life and resisting interactions that result in neutralisation, degradation or clearance of virus particles. We will explore candidate viruses with better interaction with the human immune system than type 5 adenovirus, to identify candidates suitable for (single shot) intravenous use. We will also develop simple yet effective stealthing chemistries to protect virus particles from immune attack and permit repeated i.v. administration. 2) Improve the extravasation and selective accumulation of active virus particles into the tumour environment by exploiting the physiological properties of the tumour, physicochemical properties of the particle and improve infection of target cells. We will also further develop use of cellular carriers, based on stem cells, for enhanced engraftment within hypoxic tumours and production of oncolytic virus in situ. 3) Maximise amplification, persistence and spread of virus particles throughout each tumour nodule nodules by avoiding or overcoming intracellular, extracellular and immunological barriers. Last updated 21/07/2010


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Belfast Cancer Research UK Centre (Core)
Funder: Cancer Research UK

Abstract: 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: 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