NIHRDataInsights/HRCSData huggingface dataset:
Title: Molecular aspects of prostate cancer: Interactions between the IGF system and cholesterol metabolism.
Funder: Wellcome Trust

Abstract: Prostate cancer (PCa) is the most prevalent male cancer in Europe and a major cause of cancer-related deaths. Lifestyle factors and related intermediate phenotypes have been associated with PCa development and progression in epidemiological studies, including positive associations of both circulating cholesterol and components of the IGF axis with PCa. A major problem in the treatment of localised PCa is the inability to distinguish between indolent cancers and those that will progress (heterogeneity of cancer foci may even occur within a single prostate). As some treatments for localised PCa are invasive (e.g. radical surgery and radical radiotherapy) and commonly lead to adverse effects, a better understanding of cancer progression is required to improve therapies and limit unwarranted surgery. The proposed research is an interdisciplinary approach to investigate interactions between the IGF system and cholesterol metabolism in PCa. Epidemiological techniques will inform and complement studies in cellular biology in an attempt to understand how interactions may facilitate PCa progression. Work will then extend to clinicalresearch with tissue/tumor samples. Outputs arising from this project have potential translational importance in the clinical setting, particularly in terms of prostate cancer screening and treatment.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Understanding the Cellular and Molecular Mechanisms Underlying Paracrine Tumorigenesis
Funder: Wellcome Trust

Abstract: The concept of the cancer stem cell paradigm has emerged in the field of oncology, where mutated tissue stem cells drive tumour formation through dividing to form daughter cells that comprise the bulk of the tumour1. Recently it was demonstrated that pituitary stem cells are drivers of a type of tumour known as adamantinomatous craniopharyngioma (ACP). However, in contrast to the cancer stem cell paradigm, when these pituitary stem cells aremutated they do not divide to form a tumour. Instead they induce paracrine transformation in neighboring cells, which go on to proliferate2. Thus pituitary stem cells have been shown to induce tumorigenesis in a non-cell-autonomous manner, meaning that the cells that sustain the oncogenic mutation and the tumour cell-of-origin are different. Recent evidence has suggested that mutated stem cells enter into senescence and activate the senescence-associated secretory phenotype (SASP), which may be a critical mediator of paracrine transformation. The aim of this proposal is to further our knowledge of the cellular and molecular mechanisms underlying the relationship between senescence and the initial stages of neoplastic transformation. This will be investigated in a mouse model of human ACP with the aim of providing novel insights into the origin of cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Molecular stratification of rectal cancer.
Funder: Wellcome Trust

Abstract: Cancer of the bowel, especially the rectum (back passage) is common in the UK, with 1 in 50 people suffering from this type of cancer during their lifetime. The current ways of treating this cancer are very invasive, with very large operations being performed, which are associated with long recovery periods. Some patients with cancer of the rectum have a chance of the cancer returning, despite the best type of surgery being performed and chemotherapy or radiotherapy being given. This is beca use these cancers may be resistant to the chemo or radiotherapy given. Conversely, some tumours can be over treated, where the entire back passage is removed when removal of the tumour is all that is required, leaving the back passage intact. I intend to carry out a study of tumours of the rectum, to see if we can use genetic testing of the tumour to see if we can identify which cancers will respond to local surgery only or will be resistant to chemo or radiotherapy. If we find a genetic t est that can predict this, it will lead to far less ill health from the removal and treatment of the cancer.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: CANCER AND NEOPLASMS
Title: Natural Killer cells and oncolytic adenovirus therapy in ovarian cancer.
Funder: Wellcome Trust

Abstract: Two-thirds of patients with ovarian cancer die from their disease. Previous research has shown that the immune responses elicited by patients against their cancer can influence survival. Oncolytic viruses (OVs) are a new class of anti-cancer treatment that can induce profound immune responses. These immune responses can both promote and inhibit the anti-cancer activity of OVs. I wish to investigate the role of one immune cell type, called Natural Killer (NK) cells, in ovarian cancer. In a hea lthy person, NK cells play important roles in combating virus infection. In the context of OV therapy, NK cells have the potential both to destroy cancer cells and eliminate OVs rapidly. I will assess the presence of NK cells in women with ovarian cancer and their ability to communicate with ovarian cancer cells before and after OV infection. I will also assess the ability of OV to kill ovarian cancer cells in the presence and absence of NK cells. The data generated will complement a clinic al trial of an oncolytic virus called ColoAd1 being run in Glasgow in early 2014. Therefore, my research will aid the development of this new treatment for ovarian cancer patients.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Late Stage Lead Optimisation, Preclinical Development and Clinical Trial of Lysyl Oxidase (LOX) Inhibitors
Funder: Wellcome Trust

Abstract: Pancreatic cancer has a poor survival rate. Most patients present with pancreatic cancer that has already spread. Even for the small group of patients where pancreatic cancer can be removed by surgery, the cancer usually returns within a short timeframe. Thus, there is currently no effective treatment for the majority of pancreatic cancer patients and new approaches to treat this disease are urgently needed. We have shown that the enzyme, lysyl oxidase (LOX), is important for the growth and spread (metastasis) of several cancers, including pancreatic cancer. This is a novel finding. We have synthesised compounds that can inhibit the activity of LOX and have shown that they are effective in reducing the tumour growth of pancreatic tumours in mice. We will develop these compounds further, select two drug candidates that will be assessed in a preclinical cascade leading to the choice of a drug candidate and move into early clinical trial in patients. This drug will need to be manufactured in sufficient quantities to assess its effect against pancreatic cancer in patients. Thus, we aim to discover drugs, selective for LOX, that are effective in pancreatic cancer and which could potentially be used to treat other cancers, with minimal side effects. Oral drugs are our preferred option to improve patient convenience and quality of life.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Structure-aided discovery of CaMK1D kinase inhibitors as targeted therapeutic agents for breast cancer.
Funder: Wellcome Trust

Abstract: Kinases are important targets for blocking cancer progression. Breast cancers show elevated levels of the CaMK1D kinase, but no drugs to any CaMK family member are yet available to block oncogenic activity. We have solved 3D structures of this enzyme, and discovered how other proteins and small molecules bind to it. Here we will design the first lead molecule for this target using structural, binding, and cellular assays. Spectroscopic methods will be used to visualise its interactions with drug-like molecules in order to design inhibitors that can enter cells to selectively block CaMK1D, thus minimizing potential side-effects. Our structural insights into how CaMK1D binds inhibitors, activators, and substrates suggest various avenues to design novel inhibitors that take advantage of the natural auto-inhibitory and activation interfaces. Our drug fragment approach uses chemical building blocks to construct lead molecules. This could yield efficient inhibitors that bind in new ways and offer better selectivity, as well as effectiveness against drug-resistant mutants. Cell biological tests of inhibitors with the full-length protein will provide physiologically realistic estimates of their biological activities. The ability to block tumour formation from breast cancer cells will be used to prioritise inhibitors for development as therapeutic agents.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Wellcome Trust PhD Programme for Clinicians at the University of Cambridge. The role of EZH2 in the induction and maintenance of acute myeloid leukaemia.
Funder: Wellcome Trust

Abstract: Acute myeloid leukaemia (AML) is an aggressive blood cancer with a dismal survival rate. Through recent scientific advances, our understanding of how this disease develops has improved and it is increasingly clear that altered levels of gene expression may contribute significantly towards the development of AML. We aim to investigate the role of EZH2, a gene normally involved in the regulation of other genes in control of normal blood development, in the biology of AML. To date, EZH2 has been identified as being abnormally active in breast, prostate and kidney cancer and lymphoma. We have produced preliminary data demonstrating that EZH2 is also overactive in AML. Furthermore, we think that EZH2 may be a therapeutic target as preliminary data from our laboratory, using a EZH2-targeting compound provided by Glaxo SmithKline, demonstrates reduced growth of leukaemia cells obtained from patients suffering with AML. Using a number of different laboratory and animal based techniques, we aim to demonstrate that EZH2 is required to initiate and sustain abnormal leukaemia blood cells in AML. We will identify the genes disturbed by EZH2 in AML, other mechanisms of EZH2-overactivity contributing to leukaemia and extend the preclinical testing of the EZH2 inhibitor to accelerate its use as a therapeutic.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The role of LLT1 in the liver and in hepatocellular carcinoma.
Funder: Wellcome Trust

Abstract: How cancer evades recognition by the immune system is a focus of intense research and critical to the development of novel anti-cancer therapies. We have shown that a specific protein termed LLT1 (lectin like transcript 1) is expressed on the surface of liver cancer (hepatocellular carcinoma) cells, but not present in the normal liver. This protein binds a receptor (termed CD161) found on the majority of Natural Killer (NK) cells. NK cells are white blood cells that are critical in the fight aga inst cancer as they directly recognize and kill cancer cells. The CD161 receptor inhibits the activity of NK cells. The hypothesis we stipulate is that this expression of LLT1 by liver cancer cells allows them to escape attack from NK cells. We aim to 1) investigate expression of LLT1 in the liver during disease, with specific emphasis on liver cancer; 2) investigate how the CD161 receptor functions on a molecular level and how it influences the immune cells expressing it; and 3) investigate i f LLT1 expression protects cancer cells from immune cell activity, and investigate this both in healthy individuals and patients suffering from liver cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Phase 1 trial: T4 immunotherapy of head and neck cancer.
Funder: Wellcome Trust

Abstract: In most cancers, metastasis is the commonest cause of death. However, head and neck cancer is unusual in that local spread or recurrence accounts for most death and suffering. Tumours are frequently inoperable and do not shrink in response to traditional treatments such as chemotherapy or radiation. Here, we wish to develop a new treatment for head and neck cancer that harnesses the patient's immune system to attack their own cancer. Using a blood sample, white blood cells will be treated in the laboratory with a harmless virus that introduces two new genes ( genetic engineering ). The first makes it easier to grow the cells during their time in the laboratory while the second gene enables these white blood cells to recognise and attack the tumour. To maximise safety and effectiveness of the treatment, we plan to inject the engineered white blood cells directly into the tumour. The goal of the clinical trial is to test the safety of this treatment and thereby work out what is the bes t dose for future testing. To achieve this, patients will be enrolled in groups of three and if significant side effects are not seen, successive groups will receive a higher number of cells.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Evolutionary biology of cancer.
Funder: Wellcome Trust

Abstract: This new initiative is driven by clinical need and opportunities afforded by a new vision of cancer biology. Around one in three individuals currently die of cancer and this number is anticipated to increase with extended lifespan. The burden to society, to the NHS in the UK and to the national purse is huge and daunting. Despite the advances in cancer biology and genetics and the benefit of earlier diagnosis, we are poor at predicting which of (~10%) early or benign tumours will progress to malignancy. Advanced disease remains stubbornly intransigent with emergent drug resistance highly prevalent. We propose new tactics based on evolutionary or Darwinian principles to measure, predict and ultimately thwart the evolutionary resilience and robustness of cancer cells. There is a large body of ideas and tools from evolutionary biology and ecology that can be applied to cancer. This initiative should lead to a clearer understanding of the biological basis of our vulnerability to can cer and of treatment failure, empowering the development of a different suite of tactics and therapeutics for intervention and control.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Exploring gene therapy approaches for neuroblastoma using a patient's own gamma delta T cells.
Funder: Wellcome Trust

Abstract: Neuroblastoma is a rare childhood cancer with tumours developing from the nervous system. Approximately half of patients are affected by high-risk disease and despite highly aggressive treatment regimes most children do not survive. New therapies that can target and kill cancer cells whilst avoiding harming normal tissues are therefore a research priority. Cellular therapy is a an exciting novel treatment where killer cells (T-cells) from the patients own blood are extracted and genetically modified so they are able to recognise neuroblastoma cells as 'foreign'. These modified cells are then re-injected back into the patient and are empowered to kill, multiply and survive long-term, therefore improving survival and reducing risk of relapse. Gamma delta cells are a rare type of killer cell in the blood and tissues that have many unique and advantageous properties. This project investigates gamma delta cellular therapy as we hypothesize that when genetically modified, these cel ls will confer therapeutic advantages over current strategies including better tumour responses and better long-lived protection. If successful, this will lead to a first in child study.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Identification and characterisation of mutations that predispose to myelodysplastic syndrome and acute myeloid leukaemia
Funder: Children with Cancer UK

Abstract: Myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) are related haematological malignancies. They have a poor prognosis unless a transplant is possible. They usually occur sporadically but there are rare examples of familial occurrence which provides an excellent opportunity for the identification of genetic changes that predispose to the disease. Over the years we have collected samples from 16 such families which remain genetically uncharacterised. We aim to use exome sequencing to identify the underlying defect that causes the disease in these families. The identification of the pathologic variants among the many unique bystanders identified using this approach will be challenging. However the presence of multiple affected cases in several uncharacterised families will assist in the identification of pathologically significant variants as will the finding of variants in the same gene in different unrelated affected individuals. Where gene function is unknown, candidates will be assessed by a variety of functional assays that we have available to us, including the impact of RNAi and/or ectopic expression of mutant constructs on cellular phenotypes. We will also go on to screen a larger number of sporadic cases, to determine whether or not these genes involved in familial cases also account for some of the early onset (particularly in childhood) idiopathic cases of MDS/AML. The identification of these genes will allow us to offer clear predictive diagnosis to the families involved as well as providing new insight into the causes of leukaemia.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;BLOOD
Title: The role of Thymosin beta4 in adult bone marrow stem cell transplantation for cardiac repair
Funder: Medical Research Council

Abstract: Bone marrow stem cell (BMSC) transplantation is a promising new treatment strategy for cardiac diseases, potentially by promoting cardiac repair through paracrine factor(s) secretion. Thymosin beta4 (Tß4) is highly secreted from some BMSCs and is essential in coronary vasculature development and adult neovascularisation. Furthermore, exogenous Tß4 limits infarct size and enhances cardiac functional recovery in murine acute myocardial infarction (AMI) model. Our research project will explore the role secreted Tß4 plays in cardiac repair following BMSC transplantation. Firstly, we will determine the factors regulating Tß4 secretion from murine and human BMSCs cultured under ischaemic conditions. Biological effects of secreted Tß4 on different cardiac cell types will be tested in vitro by co-culturing them with BMSC conditioned media with or without Tß4 inhibition. Cardioprotective effect in vivo is examined by injecting BMSCs from wild-type or Tß4 knockout mice and/or the conditioned media in murine AMI model. Potential target cardiac cell types labelled in transgenic mice will be tracked after AMI and wild-type or Tß4 knockout BMSC transplantation. Finally, the intrinsic human humoral T?4 response to coronary occlusion, reperfusion and subsequent BMSC transplantation and the endogenous effect on cardiac repair will be assessed using peripheral blood samples taken at appropriate timepoints from patients entered into the REGENERATE-AMI trial at London Chest Hospital. This ongoing clinical trial investigates the effects of intracoronary delivery of autologous BMSCs immediately following standard AMI care of primary percutaneous coronary intervention. The proposed project could deliver a valuable insight into the mechanism of action of cell transplantation and offer novel therapeutic targets for future development. Equally, identification of Tß4 as a secreted cardioprotective factor may establish this as a new independent therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS;BLOOD
Title: Impact of somatic mutations in patients with myelodysplastic syndrome (MDS) receiving an allogeneic hematopoietic stem cell transplant (HSCT)
Funder: Wellcome Trust

Abstract: Myelodysplastic syndrome (MDS) are myeloid haematological malignancies characterized by dysplasia, ineffective haematopoiesis and a high risk of progression to acute myeloid leukaemia (AML). The International Prognostic Scoring System (IPSS), based on blood cell counts, marrow blast % and cytogenetics categorizes patients into 4 prognostic groups: low, intermediate-}, intermediate-2 or high risk. Allogeneic hematopoietic stem cell transplant (allo SCT) remains the only potential curative treatment in MDS, but only patients with intermediate 2 or high IPSS are usually candidates for transplant due to transplant-related mortality (TRM) which can reach 15 to 30% ofthe cases. Recently, next generation sequencing (NGS) techniques of MDS genomes have identified mutations in genes implicated in RNA splicing, DNA methylation, chromatin regulation and cell signaling in approximately 3/4 of patients. Some mutations are associated with distinct clinical phenotypes, and many of them are associated with poor prognostic. However, most prognostic analyses have been performed independently of treatment, or in cohorts mainly treated symptomatically. We will determine the prognostic impact of the molecular profile on post-transplant outcome by studying molecularly profiled patients before and after the procedure.


Research activity codes: 6.4 SURGERY
Health categories: CANCER AND NEOPLASMS;BLOOD