NIHRDataInsights/HRCSData huggingface dataset:
Title: THE ROLE OF ONCOGENIC HPV E6-PDZ INTERACTIONS IN THE VIRAL LIFE CYCLE AND IN HPV-INDUCED MALIGNANCY.
Funder: Wellcome Trust

Abstract: Human papillomaviruses (HPVs) infect epithelial surfaces where they cause conditions ranging from warts to cancers at different body sites. The cancers are caused by a group of HPVs, which share an ability to interact with a small group of cellular proteins. The interactions formed by one of the viral proteins is critical for the virus to be able to replicate normally in cells, and is also important for the virus to cause cancer. We now understand the molecular basis for how the viral protein interacts with these cellular proteins, and this now allows us to design tools to specifically answer important questions. We will determine how these interactions regulate the normal life cycle of the virus and how these interactions might be modified/disrupted during cancer development. We will also investigate the normal function of these cellular proteins that have been implicated in controlling cell polarity, the loss of which is a common feature in cancer metastasis. The results from t hese studies will tell us whether these viral functions are useful targets for the development of anti-viral and/or anti-tumour agents and will also be invaluable in aiding our understanding of the processes that underlie the development of diverse human cancers.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS
Title: An investigation into the impact of Bcl-3 NF-?B signalling on b-catenin activity in colorectal carcinogenesis
Funder: Wellcome Trust

Abstract: To date few studies have demonstrated a direct interaction between the Wnt/?-catenin and NF-?B pathways (34), making the finding that Bcl-3 promotes b-catenin activity of potential importance not only for our understanding of the processes driving colorectal tumorigenesis under inflammatory conditions but also for the development of novel therapies both for the prevention and treatment of colorectal cancer. Therefore the aim of this project is to investigate the role of Bcl-3/NF-?B complexes in regulating ?-catenin activity and determine the functional significance in colorectal carcinogenesis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Dynamic cell biology programme
Funder: Wellcome Trust

Abstract: My goal is to continue using the zebrafish to learn more about how innate immune cells interact with transformed cells in vivo at the earliest stages of cancer initiation and how these compare with other functions of the immune system. I will have three main objectives: 1. To identify the changes in gene expression of immune cells when faced with transformed cells; 2. To compare these ?cancer cell triggered? changes in gene expression with immune cells exposed to wounds and/or microbial infections; 3. To investigate how the immune response to wounding impacts upon the response to a cancer cell burden, and consequently model minimally invasive cancer surgery.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Investigations into the biological function and regulation of Lgr5 in colorectal tumorigenesis and the importance of tumour stem cell adaptation to the tumour microenvironment.
Funder: Wellcome Trust

Abstract: The Wnt target gene Lgr5 is a G-protein-coupled receptor closely associated with normal intestinal stem cells and intestinal tumorigenesis. However relatively little is known about Lgr5 function in tumorigenesis and how intestinal tumour stem cells adapt and survive the harsh tumour microenvironment where oxygen is frequently limited. Our hypothesis is that hypoxia through induction of HIF-1 inhibits Wnt signaling which leads to a reduction in the expression of Lgr5 and that this is a key survival mechanism for intestinal tumour stem cells during hypoxia. Furthermore, we propose that reoxygenation leads to re-expression of Lgr5 and the selection of more malignant tumour cells and poorer patient survival. The aim of this work therefore is to investigate the biological function of Lgr5 in intestinal tumorigenesis and how intestinal tumour stem cells adapt to the hypoxic tumour microenvironment. We will further investigate whether prostaglandin E2 which is a key player in intestinal tumorigenesis and also linked to stem cell biology, interacts with the Lgr5 signaling pathway to promote intestinal tumorigenesis. This project should identify critical pathways regulating intestinal stem cell behaviour, their role in tumorigenesis and how cancer stem cells adapt to harsh fluctuating tumour microenvironments. Furthermore this research will delineate new avenues for combinational targeted therapies and chemoprevention by blocking both the Lgr5 and COX-2/PGE2 signaling pathways. These studies may also provide important insight into how tumour cells can remain dormant in patients for several years before they resume growth and threaten the patient.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Tumour Suppressor Functions of Membrane Trafficking Pathways.
Funder: Wellcome Trust

Abstract: Cancer is a disease of global impact and is one of the leading causes of death in humans. Cancers arise when normal cells begin growing uncontrollably; in severe cases these cells can spread to other locations in the body and begin growing in new sites. Cells respond to external signals by using proteins on their surface called signalling-receptors to relay this information to groups of proteins inside the cell. These signals can tell the cell to grow, to divide or to migrate. Controlling the di stribution and amount of these signalling-receptors is an important mechanism that allows the cell to respond appropriately to signals. I will look at a group of proteins that degrade these receptors and therefore play a role in damping down the cells response to outside stimulation. These same proteins are also required for normal cell division. I want to understand if loss or mutation of any of these proteins makes cells grow uncontrollably and whether this is due to failures in receptor signa lling or cell division. I also want to look at mechanisms that control the distribution of these receptors and whether this control can influence the ability of cancerous cells to migrate to new sites.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development of high-speed super-resolution STORM imaging for the large-scale analysis of transport, signaling and endocytosis in multicellular environments
Funder: Wellcome Trust

Abstract: The goal of this research is to demonstrate that temporal focusing combined with two-photon absorption and photodynamic therapy can treat a tumour that is located within a mass of tissue. In year one, the goal will be to construct the optical setup, characterise it, demonstrate automated control of the illumination parameters, and demonstrate the ability to selectively illuminate regions of a test mass such as a dye-doped gel block. In year two, the goal will be to optimise the optical se tup, and selectively generate singlet oxygen at a defined site with high spatial resolution. Diagnostic imaging methods such as stimulated Raman scattering or optical coherence tomography will be investigated for incorporation. In year three, the effectiveness of the system will be tested on cell-lines in order to demonstrate that the cells can be selectively targeted. Diagnostic imaging will be finalised and incorporated, allowing a mixture of healthy and cancerous cells (taken from cell-lin es) to be differentiated, and the cancerous cells killed. The final year will be back in the UK; the system will be reconstructed (with any modifications deemed necessary). Subject to a successful outcome, applications will be made to test the system in animal models and possibly clinical trials.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Developmemt of specific RNAse inhibitors for the treatment of haematological cancers.
Funder: Wellcome Trust

Abstract: The RNase activity of the transmembrane protein IRE1 regulates the activity of the transcription factor XBP1, a key survival factor for myeloma and other cancer cells. Modulating .the splicing of XBP1, using RNase inhibitors, can be exploited to kill myeloma plasma cells and other secretory cancers. To understand the role of the RNase domain of IRE1, a key molecule in the Unfolded Protein Response (UPR), and to develop a therapeutic strategy to selectively manipulate its function in myeloma cells using small molecules.


Research activity codes: 5.1 PHARMACEUTICALS;5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Regulation of T cell function by enzymatic proteolysis of L-selectin
Funder: Wellcome Trust

Abstract: Our experiments are directed at enhancing the potency of adoptive T cell immunotherapy (ACT). To date, all three applicants have made a series of independent observations on different aspects of T cell biology following genetic manipulation of mouse T cells. Each of these genetic changes has had the effect of significantly promoting anti-tumour immune responses. A natural progression of these findings, to be pursued in this grant, is to explore in the context of adoptive T cell immunotherapy, the potential overlapping, additive or synergistic effects of combining these genetic manipulations of T cells. Specifically, in this proposal we will: Determine whether adoptive transfer of CD8 T cells with maintained L-selectin and/or deficiency in SHP-1 induces regression of vascularised tumours in mouse Determine whether the removal of Tregs from the tumour bearing hosts has an additional or synergistic effect on CD8 mediated tumour regression in mice Determine whether human CD8+ T cell reactivity to tumour antigens can be similarly modified by maintained L-selectin and/or SHP-1 deficiency and whether sensitivity to Tregs is altered


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Manipulating T lymphocyte homing and activation for cancer immunotherapy.
Funder: Wellcome Trust

Abstract: The harnessing of one s own immune system, termed immunotherapy, to treat a cancer is an extremely attractive proposition because of the potential for combining high selectivity with low toxicity. Immunotherapy has progressed significantly in recent years, as our understanding of the targeting of tumour cells by the different cell types that comprise the immune system has improved. Nevertheless there is considerable need for more improvements in order to ensure this form of treatment is more w idely and effectively applied. Independent research conducted by our combined groups over the past decade has identified three separate components of the immune system capable of limiting tumour growth. We are now seeking to exploit our findings by combining these three approaches that will have the effect of allowing more T cells to be recruited and to efficiently reach the tumour but also to function more effectively in attacking cancerous cells once present in the tumour. Our work has pote ntial for the development of novel immunotherapies for treating a range of cancers.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Interactions between co-occuring leukaemogenic mutations identified in acute myeloid leukemia genomes
Funder: Wellcome Trust

Abstract: The proposed work will study how co-occurring mutations, identified in recent whole genome sequencing studies of human AML, operate to promote leukaemogenesis and in so doing facilitate rational drug design against this disease. In particular, I propose to study conditional mouse models of NPM1c, IDH1-R132H and NRAS-G12D, to understand how these mutations operate in leukaemogenesis. The study will involve detailed analyses of the in-vivo effects of each mutation individually, as well as in co mbinations of 2 and all 3. The experiments will delineate the combinatorial molecular and cellular effects of these mutations on the haemopoietic compartment and on the mechanisms underlying cellular transformation. Additionally, I propose to perform a complementary study to identify genes that collaborate with mutant FLT3 to cause AML using transposon insertional mutagenesis in Flt3-ITD mice, in a similar fashion to my recent work with Npm1c mutations. My findings will be compared to da ta from well-studied collections of human AML and parallel sensitivity studies against 200 anti-cancer drugs will be performed on cell lines derived from these models to identify drugs effective against such leukaemias. I anticipate that the proposed work will deliver a deep understanding of AML and define routes for its therapeutic targeting.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The Open Microscopy Environment: Image informatics for Biological Sciences
Funder: Wellcome Trust

Abstract: Quantitative imaging is now used to measure the dynamics of molecules in cells, the development of embryos, the progression of cancer and other diseases, and the responses of biological systems to small molecule inhibitors and drugs. The resulting data is large, complex, and difficult to access, analyse and share using conventional desktop software. Our project, the Open Microscopy Environment (OME) develops open data format specifications (OME-XML and OME-TIFF), a file translation library (Bio -Formats), and a platform for data management, analysis, visualization and sharing (OMERO). Initially built for light microscopy, we have successfully extended these tools into high content screening and electron microscopy. In this project, we will extend the coverage and utility of OME-XML, Bio-Formats, and OMERO to handle the new types of data used in bioimaging. We will add support for complex data visualization and a data publishing facility to OMERO to further promote open data shari ng. We will place developers in laboratories with specific expertise in diverse data types, image analysis, or large-scale computational analysis to ensure they are integrated into OME and available to the community. We will deliver an openly and freely available enterprise solution for image data access and management.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Notch and APRIL-mediated drug resistance in distinct molecular subgroups of multiple myeloma.
Funder: Wellcome Trust

Abstract: Multiple myeloma is a rare bone marrow cancer. It causes weak, painful bones, kidney disease and damages the immune system. It is treated with chemotherapy, which is usually effective in controlling the disease, sometimes for years. However the disease always returns and is eventually fatal. Recent scientific evidence shows that some myeloma cancer cells are more resistant to chemotherapy. These cells may then become active after chemotherapy has finished and produce new cancer cells. This r esearch will study these cancer cells to try and understand how they resist chemotherapy. Other research by our team has looked at the effect of specific proteins and chemicals in the body that seem to help the cancer cells survive. We will explore exactly how this happens and test whether blocking the actions of the proteins will make the myeloma cells more sensitive to chemotherapy treatment. Myeloma patients have bone marrow tests performed during their treatment. Our study will use bone marrow samples taken from patients having these tests as part of their treatment.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The role of Notch signalling in the tumour stroma microenvironment of cholangiocarcinoma.
Funder: Wellcome Trust

Abstract: Cholangiocarcinoma is a particularly aggressive form of liver cancer arising from the cells of the bile ducts (the bile ducts transport a substance known as bile produced by the liver to the intestine). This cancer has proved resistant to conventional chemotherapy drugs and most cases are not suitable for curative surgery due to its rapidly invasive nature. New approaches to treatment are urgently needed. Scientific study of this cancer has proved problematic due to the lack of a representa tive experimental model in rodents. The availability of new mouse technology now allows us to switch off genes on demand in particular cell types. We plan to use this to switch off a gene in the cells of the bile duct known as p53 that normally regulates genetic damage to the cell preventing it from becoming cancerous. This combined with delivery of a toxic compound will result in the mouse developing cancer. Once this model is developed and tested, we plan to use it to study a molecular s ignal in the cell known as Notch which is known to be important in the development of cancer, and is proving to be a promising and realistic target for new anti-cancer treatments.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: A leading role for macrophages in breast cancer metastasis.
Funder: Wellcome Trust

Abstract: A cancer is not simply a solid mass of cancerous cells; it functions more like a rogue organ . Within a solid tumour one can find cancer cells, but also fibroblasts, blood vessels and white blood cells (immune cells) that are helping the tumour to survive. The overall goal of the fellowship is to gain a better understanding how a specific immune cell subset, the macrophage, is stimulated to assist the cancerous cells to enter the blood stream, spread through the body and start growing at a s econdary site (metastasis). I will focus on two main key goals: 1) Understand where the macrophages that are supporting the tumour are originating from. 2) Determine how fibroblasts and the cancer cells are influencing immature macrophages to develop into macrophages that are helping the cancer to metastasise.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Preclinical and Clinical Development of BRAF Inhibitors.
Funder: Wellcome Trust

Abstract: BRAF is a validated therapeutic target present in approximately 50% of malignant melanomas and in a number of other cancers. Various drug development programmes for the treatment of mutant BRAF-driven malignancies have been initiated; the most advanced inhibitor in this class is PLX4032, which is currently being assessed in a Phase III clinical trial against melanoma harbouring a mutant BRAF gene. Although most patients respond to treatment with PLX4032, in all cases the tumours relapse after some months due to the development of resistance to PLX4032. Furthermore, around 30% of the patients develop squamous cell carcinoma (SCC) or keratokantoma as a side effect. These data highlight the need to develop further BRAF-targeted therapeutics for melanoma. We synthesised 3 novel BRAF inhibitors at the Institute of Cancer Research and demonstrated that they are effective in tumours driven by mutant BRAF. In addition, we have shown that the characteristics of these inhibitors would allow these compounds to be used in melanomas that are not driven by BRAF but by mutant NRAS, and also to reduce the incidence of SCC in BRAF-driven melanoma patients. We propose a preclinical and clinical development programme to establish the pharmacokinetics of 3 and toxicity profiles for 2 of the BRAF inhibitors we have developed to allow us to progress one of these drugs to a melanoma clinical trial at the Royal Marsden Hospital.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Investigating how Eph receptor expression alters migration and invasion of prostate cancer cells
Funder: Wellcome Trust

Abstract: The overall goal of my research is to investigate how Eph receptor expression alters migartion and invasion of prostate cancer cells. We know the Ephs and Ephrins are important mediators of cancer progression, but the molecular mechanisms by which they function have not been fully characterised. I have two aims: investigate how exposure of prostate cancer cells to hypoxia alters the expression of Ephs and ephrins and how this leads to altered levels of cell migration and invasion (by exposing prostate cancer cells to hypoxia and characterising Eph and ephrin expression profiles before undertaking a number of migration and invasion assays in hypoxia. second is to identify the molecular mechanisms by which EphB2 prevents prostate cancer progression: migration and invasion assys on prostate cancer cells manipulated for EphB2 expression. Characterise EphB2 mutations know to correlate with prostate cancer. Finally I will undertake SILAC mediated quantitative mass spectrometry to build a global picture of EphB2 signalling in prostate cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Infection, Immunology and Translational Medicine - 'Establishment of a transgenic zebrafish model to study the innate immune response to melanoma'
Funder: Wellcome Trust

Abstract: Although immune mechanisms, such as cytokines produced by immune cells in response to the tumour environment, may provide protection against cancer by elimination of transformed cells, they may also aid tumour development by immunosuppressive mechanisms. Epigenetic mechanisms that alter chromatin landscape, enabling the unwrapping of transcriptional programs play important roles in all cellular processes including immune response mechanisms and carcinogenesis. It remains difficult to assess the overall effect of innate immunity during early tumourigenesis since direct in vivo models for evaluating the effects ofthese phenomena on initial tumour growth are missing. We propose to develop a melanoma model in zebrafish to study the initial host immune response to melanoma with particular focus on epigenetic changes. Key Goals 3.1 Establish a zebrafish model system to study the innate immune response to melanoma. 3.2 Characterise the interaction of neutrophils and macrophages with oncogenicmelanocytes as compared to normal melanocytes in vivo. 3.3 Carry out a genome-wide analysis of macrophages and neutrophils' response to melanoma compared to control melanocytes. i. Identify differentially expressed genes by comparing transcriptomes of innate immune cells ii. Identify changes at the epigenomic level in innate immune cells that may be resulting in differential cytokine expression 3.4 Investigate findings in melanoma patients.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS