NIHRDataInsights/HRCSData huggingface dataset:
Title: What is the role of CD8 regulatory T cells in anti-tumour immune responses in hepatocellular carcinoma?.
Funder: Wellcome Trust

Abstract: One out of three deaths in the world related to cancer is due to liver cancer. Treatments for liver cancer are often limited and as a result outcomes are poor for the majority of patients. It has been acknowledged that the immune system is able to recognise a wide range of cancers. However, cancer cells are very good at evading the immune system and one possible mechanism involves the inhibition of the immune system. Special suppressive immune cells are normally present to prevent over activ ation of the immune system. It has been suggested that cancer cells are able to hijack such cells to suppress the immune system. Our project is designed to try and work out if suppressive immune cells are involved in preventing the immune system to flight against cancer. If we can identify the presence of suppressive immune cells in liver cancer and work out how they function, we would then be able to use this information to develop treatments that block the effect of these cells. Hence, th is would allow the immune system to correctly recognise cancer cells and slow down or stop its growth.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Evaluation of combinatorial drug strategies to combat de novo and acquired drug resistance to targeted molecular therapies.
Funder: Wellcome Trust

Abstract: Our understanding of the biology of human cancer has enabled the introduction of new drugs to treat this disease over the last decade that are completely different from standard chemotherapies. These drugs interfere with the specific cancer machinery in the cell that has gone awry to produce a cancer. There are a few striking examples of where this has completely changed the outlook for patients with particular types of cancer. However for the majority of patients our increased knowledge of the genetics and biology of cancer has unfortunately not been able to change our treatments from standard chemo and radiotherapies. The goal of this project is to identify new combinations of drugs targeted to the cellular machinery that Is deranged in cancer cells in order to overcome resistance to treatment. These drugs for the most part are already available or in clinical trials, but put simply have not been used optimally as we have had no way of identifying who benefits most from receiving each drug, as every cancer is genetically different. By examining the detailed genetics of these cells across many cancer types for the first time in such a detailed and systematic way we hope to produce new biological markers that predict their sensitivity to a particular combination of drugs.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Analysis of the involvement of AIP in tumourigenic signalling pathways in pituitary tumours and its role as a circulating peptide.
Funder: Wellcome Trust

Abstract: The pituitary gland is an important organ for regulating our hormones. This gland can develop benign tumours leading to effects on neighbouring vital organs e.g. the eye and generalised effects of hormone excess or deficiency. A new gene, (AIP) has been identified as being responsible for pituitary tumours which run in families. Patients children may inherit this faulty gene, putting them at risk of pituitary tumours too. Patients with this gene are more likely than pituitary tumour patients wit hout it, to develop highly aggressive tumours which are resistant to treatment, via an unknown mechanism. Our project has two parts: firstly in the laboratory well make the AIP gene over-active in one set of pituitary tumour cells and under-active in another, to see how it affects other genes possibly involved in tumour development. This allows us to understand how lack of the AIP gene causes tumours. The second part concerns the presence of AIP protein in the blood - previous experiments co nfirmed its presence. Well study the factors that alter its circulating level in patients and healthy volunteers to understand AIPs role. Additionally, well study patients with other pituitary diseases to see if AIP levels are a good marker of disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: A novel generation of oncolytic Vaccinia viruses armed with immunomodulatory genes to treat and prevent the recurrence of solid tumours.
Funder: Wellcome Trust

Abstract: A novel, promising anti-cancer therapy involves the use of viruses that have been designed to target and kill tumour-cells without affecting normal cells. These oncolytic viruses alone are often incapable of completely eradicating a tumour. Extra help is required and may be provided by the patient's own immune system. However, cancer patients, particularly those with advanced disease are often immunocompromised and their immune system thus requires a boost for it to be able to attack tumour-ce lls. Widespread stimulation of the immune system may however cause harm to the patient. One way of localizing the immune response to within the tumour is by the use of oncolytic viruses armed with genes that produce immunity boosting proteins (called cytokines). Because these viruses have been engineered to only replicate in tumour cells, the cytokines will only be expressed within the tumour and will focus the immune response into the tumour environment. I will genetically attach such cytokine genes to viruses that have been engineered to be tumour specific and safe. The feasibility and safety of these novel viral constructs will be evaluated in different cancer models. Ultimately, I aim to develop an effective viral immunotherapeutic strategy to eradicate cancer and prevent its recurrence.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Exploiting the contributions of PI3-kinase signalling and EZH2 histone methyltransferase to drug resistance and tumorigenesis in glioblastoma.
Funder: Wellcome Trust

Abstract: The mainstay of treatment for the deadly brain tumour glioblastoma in radiation plus the chemotherapy drug temozolomide. We have identified a novel mechanism by which a patient's tumourmay not respond to the drug, reducing the effectiveness of the treatment. We propose to systematically investigate the different components of the pathway we believe to be active in a subset of tumours, and which confers a particularly poor prognosis in these patients. We aim to identify which combinations of novel targeted agents may best be used to overcome this resistance, such that we may be able to improve the survival of glioblastoma sufferers.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Identification of genes involved in the differentiation of liposarcomas as novel therapeutic targets.
Funder: Wellcome Trust

Abstract: Liposarcomas (LPS) are a heterogeneous group of tumours that show features of adipocyte differentiation. Well differentiated (WD) LPS and de-differentiated(DD) LPS represent a continuum of disease and together comprise the most frequent subtype of LPS in adults. WDLPS tend to have a goodoutcome whereas DDLPS reoccur and metastasize with an associated poor outcome for patients. The aim of the project is to identify novel therapeutic targets for the treatment of liposarcomas. Our working hypothesis is that gene products involved in maintaining the undifferentiated adipocyte phenotype of liposarcomas are a potential therapeutic target for 'differentiation therapy' of these tumours. Gene expression profiling of LPS with different histologicalcomponents, cell lines and normal tissues as well as mining of publically available data will identify differentially expressed genes linked to the differentiation process. These will be investigated in vitro and in vivo as new molecular targets for therapy.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: PRaVDA (Proton Radiotherapy Verification and Dosimetry Applications) - Integrated computed tomography and dosimetry instrument for proton therapy
Funder: Wellcome Trust

Abstract: Radiotherapy is a fundamental weapon in the battle against cancer with some 40% of patients receiving it as part of their treatment. Standard x-ray therapy and proton beams work through selective cell destruction. Proton therapy offers unique clinical advantages. As the proton travels, only a small amount of dose is delivered along its path - unlike conventional radiation treatment - and most of the dose can be delivered at a precise distance in tissue. Consequently there is a much-reduced residual dose in surrounding healthy tissue and deep-seated tumours can receive a higher dose. Due to its potential for increased treatment accuracies, proton therapy is especially beneficial where tumours lie close to vital structures in the body or for young people where potential for developing secondary cancers later in life is much reduced. The tightly focused deposition of proton beams has many advantages, but it also creates potential risks. Errors in the planning and/or delivery of the treatment could result in the high dose being deposited in healthy tissue. Our instruments will overcome these problems and so encourage the wider use of this new exciting therapy. By using new discoveries in solid-state imaging and detection, we will develop detectors to provide accurate dose information during treatment, measure the beam energy before and after the patient to provide images during actual treatment - proton radiography, and record individual proton tracks to allow full 3D images of the proton interactions with the tumour. The last is termed proton-computerised tomography (pCT), equivalent to the more conventional x-ray CT scans but showing in real-time treatment profiles of an individual tumour and where the radiation is absorbed the 'holy grail' of proton radiotherapy treatment. Our work will lead to more effective treatment of cancers not only in children or where tumours are located close to our vital organs (such as the optic nerve or the spine) but also one of the most common, and in later stages difficult to treat, cancers namely prostate cancer. Proton therapy with improved imaging during treatment should result in shorter treatment regimes for patents and less distress.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Using Genetics in Mainstream Medicine to Deliver Personalised Care for Cancer Patients.
Funder: Wellcome Trust

Abstract: Knowledge of the genetic variants associated with cancer causation and treatment has considerable clinical impact. It is increasingly essential for the optimal management of people with cancer. Unfortunately, cancer gene testing is currently severely restricted. There is no NHS gene test available for over half of the known cancer predisposition genes and there are tight restrictions on access to gene testing. The restrictions are because current gene testing methods are laborious and expensive. Recently, new technologies have emerged that make gene testing much faster and cheaper. We will use these new technologies to develop a new test that covers all genetic variants of relevance to cancer. The test is called the CaPS panel and it will be able to test all cancer genes at lower cost than a single test with current methods. We will also develop the necessary analytical tools for reporting the results of the CaPS panel to doctors to use in patient management. We will also undertake doc tor, patient and public education, so that the benefits and implications of CaPS panel testing are appreciated. The availability of CaPS panel testing will rapidly increase the number of people able to benefit from cancer gene testing.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: The role of aberrant RNA processing in the pathogenesis of Multiple Myeloma.
Funder: Wellcome Trust

Abstract: Myeloma is a cancer of the immune system with multiple complications. Although the disease can be controlled to some extent, it remains essentially incurable. New treatments are therefore required. However, to design new treatments, we need to better understand mechanisms of the disease. Recent work sequencing cancer genomes is unearthing previously unrecognized mechanisms of cancer development. This is the case for myeloma, in which genes involved in processing RNA (molecules involved in tra nslating cellular DNA blueprints into proteins) have been found to be recurrently mutated. This suggests that these mutations are important for the disease and may represent a potentially novel vulnerability by which myeloma can be targeted. However, it remains to be understood how these mutations contribute to the disease. This proposal seeks to understand the mechanisms of these mutations. The normal function of one of these genes is well understood, but the function of the other is largely unknown. This project will therefore initially attempt to understand the normal role of the unknown gene by deleting it from experimental cells. Then, novel sequencing technology will identify the RNA pathways affected by mutations of both these genes in samples from patients with myeloma.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Quantitative proteomic dissection of genetic aberrations In PDAC development.
Funder: Wellcome Trust

Abstract: Pancreatic cancer is composed of several different types of cell. These different cell types communicate with each other and concurrently expand as the disease develops. If we can understand how these different cells talk to each other we can make drugs to block their communication as treatments for pancreatic cancer. To study their communication we will individually 'label' each cell type with a specific marker and then mix these cells together. When combined the different cell types will talk to each other. We will monitor this conversation by analysing changes in communication molecules within the cells. As the cells are individually labelled before they are combined, we can distinguish between each side of cellular discussion. We will use these results to record the dialogue between the two cell types. To ensure the dialogue is accurate, we will compare it to real pancreatic cancer found in mice. Accurate communication patterns will be proposed as new drug targets.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Loss of redundant mRNA export pathways in cancer cells: An investigation of this novel therapeutic target and prognostic biomarker.
Funder: Wellcome Trust

Abstract: Cancer is one of Britain's biggest killers. The normal human cell provides an environment for genes to be made into proteins used to promote and maintain our survival. A key step is to take the mRNA (a complimentary product of DNA) out of the nucleus and into the cytoplasm to be made into a protein. To facilitate this process there are exporter proteins that provide taxi-rides for mRNA to optimise this transport. There are a number of key exporter proteins already identified, and we are interrog ating the properties of novel exporter protein pathways which are not required by normal cells, but on which cancer cells seem dependent. We aim to demonstrate this dependency and see whether we can identify inhibitors which would stop these pathways in cancer cells. We may then selectively kill cancer cells in the body. We will also assess whether these novel mRNA exporter proteins might be used in a diagnostic tests for cancer and help clinicians decide on the best course of action for patient s diagnosed with cancer.


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: Transformation of Myelodysplasia to Secondary Acute Myeloid Leukaemia.
Funder: Wellcome Trust

Abstract: Myelodysplasia (MDS) is a disorder of defective blood cell production. There are ~3000 new cases/ year in the UK. Very few patients are cured of the disease. In ~40% patients, it progress to secondary Acute Myeloid Leukaemia (sAML) and this is a common reason why patients develop AML. Only ~2% patients with sAML survive. We therefore need to improve therapy. Furthermore, study of MDS and sAML will help us understand the step-wise process by which cancer arises. Humans produce ~10 billio n new mature blood cells daily to survive. Blood cells are produced from a small pool of self-renewing blood stem cells. These produce a larger number of descendent progenitor cells that mature into the blood cells we need. MDS and sAML mainly arise through random changes (mutations) in genes that regulate blood cell production. We plan to generate a compendium of the genetic mutations present in patients' DNA at both stages of their disease and assess the impact of these mutations on diff erent blood stem and progenitor cells. This necessary information will provide a rational platform for future developments to improve patient care (e.g. prognostic testing in patients with MDS and new therapies to treat both conditions).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The radioprotection of composite tissue free flaps using ex vivo gene therapy.
Funder: Wellcome Trust

Abstract: Radiotherapy after surgery for cancer reduces the risk of the cancer returning at the site of operation. After extensive surgery to remove a cancer reconstruction is required for functional or aesthetic reasons, using a block of tissue (a flap) from elsewhere in the body. Radiotherapy damages the tissue flaps that are used for reconstruction leading to scarring, tissue death, infection and anatomical distortion requiring further surgery to fix. Reconstructions can be delayed until a few months a fter radiotherapy but delayed reconstructions result in more operative procedures, more time in theatre and worse aesthetic outcomes. Delaying can also be psychologically harmful to patients who have deformities as a result of surgery for cancer. My project aims to protect the flaps used for reconstruction from the harmful effects of radiotherapy. I aim to do this using a gene therapy approach by delivering genes to the flap that will protect it from the harmful effects of radiotherapy. These genes are delivered to the flap by virus particles, which are capable of entering the cells of the flap to deposit the genes in their nucleus. The cells will then use this genetic information to produce proteins that will protect it from radiation damage.


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Investigation of Tankyrase Inhibitors to Block Wnt Signalling as a TherapeuticStrategy for Sarcomas
Funder: Wellcome Trust

Abstract: Sarcoma sensitivity to tankyrase inhibitors will be investigated by screening a panel of sarcoma cell lines covering diverse histologies with compounds fromthe lead series of ICR tankyrase inhibitors. Sensitivity will be compared to activity of the Wnt pathway to confirm if tankyrase inhibitors are more effective in cells with high Wnt pathway activity. Pathway activity will be measured using immunoblots for active ?-catenin, TOPFLASH reporter assays and Wnt target gene expression profiling. Sensitivity will also be compared to cell line dependence on the Wnt pathway using dominant negative TCF4 expression to block expression of Wnt target genes. Biomarkers that predict sensitivity will be found by correlating the data for drug sensitivity to mutation and gene expression profiles available from online databases, and potential biomarkers will be confirmed by RT-PCR and immunoblots. Further investigation of the involvement of validated biomarkers in determining sensitivity will be performed using RNAi knockdown and cDNA overexpression of the gene in question. Mechanisms of resistance will be investigated using combinations of clinically relevant drugs with tankyrase inhibitors to identify compounds that act synergistically to increase the effect of tankyrase inhibitors.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Modelling TEL-AML1 Childhood Acute Lymphoblastic Leukaemia using Human Pluripotent Stem Cells.
Funder: Wellcome Trust

Abstract: Cancers arise due to mutations in multiple genes. The earliest mutations (first-hits) are important to study because they fundamentally alter the function of the cell and they are present in every cell of the cancer. As this pre-cancer develops it picks up further mutations (second-hits), some of which co-operate with the first-hits to produce the established cancer. By the time a cancer is diagnosed there are many mutations, making understanding their relevance complex. To understand how a leukaemia starts requires a model of the interplay between both the first-hit mutation and the cellular make-up of the specific cell type in which it arises. Childhood leukaemias are particularly interesting to study: the mutations are simple and well known and probably specifically affect embryonic blood cells that are different to adult blood. Understanding the early stages of childhood leukaemia needs a simple, but authentic model. We will therefore employ human pluripotent stem cells to recreate embryonic blood formation in a dish and use state-of-the-art genetic engineering to accurately recreate the mutations present in the commonest form of childhood acute lymphoblastic leukaemia (ALL).


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Two-Dimensional Laser Mass Spectrometry: New Proteomics for Clinical Biology of Breast Cancer and Other Diseases.
Funder: Wellcome Trust

Abstract: This project is concerned with proteomics, a branch of science that studies protein structure and function. Proteins are vital parts of living organisms that are involved in all biochemical processes within cells. Determination of sequence and modifications of amino acids in proteins is essential for understanding protein functions within organisms and is often crucial for successful drug design. One of the most powerful methods of proteomics is mass spectrometry (MS) that seeks to establish pro tein sequences by analysing mass-to-charge ratios of gaseous charged peptides/proteins and their fragments. Here we will develop the first of its kind two-dimensional MS (2D MS) that will show directly which pairs of charged fragments originate in the same peptide dissociation process, leading to rapid and confident deduction of the amino acid sequences. This novel laser-based proteomic technology will revolutionise our ability to analyse protein molecules related to development and treatment of human diseases. We will apply the 2D MS technique to investigate resistance of breast cancer to endocrine therapy. Breast cancer is the most common type of cancer affecting women in the world and our planned 2D MS proteomic study can lead to strong improvement in medical treatment of this disease.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS