NIHRDataInsights/HRCSData huggingface dataset:
Title: Interplay between SWI/SNF remodelling complex and hypoxia in cancer.
Funder: Wellcome Trust

Abstract: Recent advances to genome sequencing have made it possible to catalogue the network of genetic changes occurring in cancer cells. These studies have confirmed the importance of established tumour suppressors such as TP53. They have also detected mutations in factors previously less strongly linked to cancer. Perhaps the most spectacular example of this is the finding that mutations to components of the human mating type SWItching/Sucrose Non Fermenting (hSWI/SNF) ATP-dependent chromatin remodelling complex occur at a frequency comparable to TP53. It is the aim of this proposal to gain insight as to why mutations to components of this complex contribute to tumour progression. We will focus the study on the PBRM1 and ARID1a subunits that arefrequently mutated in renal cancers and their roles in the cellular response to hypoxia. The hSWI/SNF complex is known to participate in regulation of Hypoxia Inducible Factors and their targets transcription, which is a key process required for adaptation to the hypoxic environment within solid tumours. Some of the approaches used to study the effects of SWI/SNF mutationsin hypoxia, including chromoimmunoprecipetiation (ChIP) will be applied genome-wide in order to characterize the behaviour of hypomorphic SWI/SNF complexes in a non-biased fashion.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Development of compounds that inhibit RAS-effector protein-protein interactions in cancer using a single antibody domain drug surrogate emulator approach
Funder: Wellcome Trust

Abstract: The RAS family of oncogenes is among the most frequently mutated in human cancers. As part of our work to develop technologies to modulate protein-protein interactions inside cells using minimal antibody fragments, we have characterized an anti-RAS VH segment whose binding site covers the region of RAS where signal transduction effector proteins bind (the switch region). In mouse models of lung cancer, we have shown that the anti-RAS VH inhibits tumourigenesis, thus validating mutant RAS-effector interaction as a therapeutic target and demonstrating that the VH interface is a drug surrogate. We showed, by X-ray crystallography and site-directed mutagenesis, that the VH interaction surface corresponds to 6-8 essential amino acids, and site. Using two different approaches, we have recently identified small molecules that bind to RAS at the same point of contact as the anti-RAS VH (from a fragment library screen and from a diverse compound library screen). The work of the proposed programme is to develop these hits to leads and ultimately identify a preclinical development candidate by chemical modification. We will iteratively develop the hits to obtain greater binding efficacies and biological compatibility using a range of bioassays and mouse preclinical models.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: The importance of the Notch signalling pathway and its interactions in the maintenance and progression of Chronic Myeloid Leukaemia.
Funder: Wellcome Trust

Abstract: Blood cells are produced by stem cells in the bone marrow. Stem cells are immortal cells that constantly divide and produce new cells. Chronic Myeloid Leukaemia (CML) develops due to intrinsic problems within a stem cell, which becomes abnormal, and multiplies rapidly, evading mechanisms that normally control cell numbers. About 30% of patients with CML will fail initial therapy, either due to these stem cells becoming resistant or the patient becoming intolerant to treatment. Progression is associated with high mortality, as it behaves like an aggressive acute leukaemia. The causes for this are not fully understood. All cells have a set of instructions that tell them what to do and when to do it, based on signalling pathways within the cell; alterations which switch these pathways on often give rise to cancer. The aim of this proposal is to explore, one of these pathways, the Notch pathway, which is altered in progressive CML. This pathway is important for maintaining stem cell s. We will characterise this pathway in CML and also investigate the interactions which occur with other pathways known to be active in stem cells and leukaemia. This will determine if the Notch pathway is a potential future therapeutic.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The role of T cell exhaustion in cutaneous squamous cell carcinoma.
Funder: Wellcome Trust

Abstract: Skin cancer is the most common cancer in the UK and a significant health problem, therefore research into skin cancer biology is essential to allow development of new treatments. Sun exposure is an important cause of skin cancer, but weakened immunity also allows growth of cancers, especially squamous cell cancer (SCC) of the skin. We have shown that cancer-fighting immune cells called CD8+T-cells accumulate in skin SCC but have reduced ability to proliferate. As SCCs persist despite the presenc e of CD8+T-cells, this suggests that the CD8+T-cells have lost their cancer-fighting ability, and we hypothesise that this is primarily due to a process called 'T-cell exhaustion'. In this study, T-cell exhaustion in skin SCC will be investigated by looking at markers of exhaustion on CD8+T-cells, and whether these cells are dysfunctional and have lost their ability to secrete chemicals which kill tumour cells. Experiments will be performed to study the molecules in CD8+T-cells in SCC which regu late T-cell exhaustion, and the factors in the tumour that cause this to happen. Investigations will also examine whether inhibiting T-cell exhaustion restores CD8+T-cell function in SCC, so as to enable new treatments for SCC that target T-cell exhaustion to be developed in future years.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The metastatic cascade: macrophages lead the way
Funder: Wellcome Trust

Abstract: In breast cancer the survival rate of women with metastatic disease has not changed for 30 years indicating the need to different treatment strategies. While research has largely focused upon tumor cells it has become apparent that progressive modification of the stromal microenvironment is equally as important in tumor progression to malignancy as the changes in the tumor cells themselves. In this environment macrophages are particularly abundant and I showed that they promote tumor progression to malignancy. These effects are through stimulation of angiogenesis, promotion of tumor cell invasion and intravasation, suppression of anti-tumor immune responses and at metastatic sites, promotion of extravasation and their subsequent tumor cell establishment and persistent growth. The aims of this application is to define the molecular bases of these activities through the metastatic cascade. This will enable development of macrophage sub-population specific reagents that can be combined with conventional therapies to improve the outcome of patients with metastasis disease. My four specific aims will elucidate the mechanisms of macrophage action on angiogenesis and tumor cell migration, invasion and intravasation in the primary tumor. At bone and lung metastatic site I will determine the mechanisms behind the macrophage stimulation of seeding and persistent growth. Strategically I will use innovative in vivo imaging combined with conditional genetic ablation in macrophages of ke y signaling molecules in mouse models. This will ascribe specific biological functions to individual macrophage populations. These studies will also be translated to human breast cancers and their modeling in humanized mice.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Mutational signatures of DNA damage and repair processes.
Funder: Wellcome Trust

Abstract: Most human cells acquire mutations in their DNA throughout life. These are called somatic mutations and they occur in normal cells, cancer cells and cells from other diseased tissues. Somatic mutations cause human diseases, particularly cancer. They themselves are caused by exposures to factors such as sunlight and tobacco smoke. Each cell contains a complex DNA repair machinery that reduces mutation accumulation. When this machinery goes wrong, cells can acquire even more mutations, further con tributing to disease development. Although we know that sunlight and tobacco can cause mutations, we do not know the causes of most somatic mutations. New DNA sequencing technologies have shown that, in cancers, there are many different mutation patterns (signatures), suggesting that there are many different processes causing them. Here, we bring together scientists with distinct and complementary expertises to define mutational signatures caused by many chemicals and types of radiation, and by various types of defective DNA repair in model systems These mutational signatures will then be compared with those from normal and diseased human tissues to give clues to their origins. This work will advance our understanding of how somatic mutations cause disease and could also suggest new avenues for diagnosis and treatment.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Fragment-based lead discovery against the protein-protein interaction between Aurora A and TPX2 for the treatment of cancer
Funder: Wellcome Trust

Abstract: Cancer is a disease caused by cells with mutated genes that allow them to grow and divide in an uncontrolled manner generating a tumour. The process by which a cell divides is controlled by a number of large molecules called proteins. A pair of proteins, Aurora A and TPX2 play a key role in this process. There is evidence from a number of scientific groups that a chemical compound Project Details 9 capable of preventing these two proteins from interacting may have utility as a drug for the treatment of cancer. Using powerful approaches we have pioneered in Cambridge, we have identified some starting points for our work; these are small chemical compounds that are capable of blocking the interaction, but only at high concentrations. We propose to make further examples in order to optimise the efficiency with which these compounds operate. We will ensure that other properties of the molecules are suitable for them to work in animal models of cancer and to be developed into a new class of anti-cancer drug. Our work will make extensive use of X-ray crystallography that allows us to see' our molecules binding to one of the protein targets and helps us design improved compounds.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Redirecting T cells with a Chimeric Antigen Receptor against ROR1 to target Chronic Lymphocytic Leukaemia.
Funder: Wellcome Trust

Abstract: Chronic Lymphocytic Leukaemia (CLL) is the commonest leukaemia in the developed world and despite advances in treatment remains incurable in the vast majority of patients. We aim develop a new treatment approach by using gene therapy to reprogramme patients own immune system to fight CLL by introducing a set of genes into specific immune cells, called T cells, which would allow them to recognise a protein on CLL called ROR1 and kill them. For this to become reality we need to have the bas ic science, groundwork & safety firmly established; which our key goals aim to deliver by: 1. Demonstrating engineered ROR1 recognising T-cells can effectively kill cells expressing ROR1 in a mouse model of CLL. 2. Demonstrating safety by showing that engineered T-cells only kill cells with ROR1 and not healthy human cells. 3. Develop the necessary method to allow production of a large numbers of engineered T-cells from humans without affecting their function and this would have to be undert aken whilst meeting strict quality assurance and control criteria. Successful completion of these key goals would allow us to undertake a future clinical trial aimed at helping patients suffering from CLL.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Nicotinamide Nucleotide Transhydrogenase (NNT) as a novel molecular target in the treatment of adrenocortical carcinoma.
Funder: Wellcome Trust

Abstract: Adrenocortical carcinoma (ACC) is an aggressive malignancy with limited treatment options. New treatment avenues are urgently required. One such avenue may relate to recent research showing that patients with congenital loss of adrenal function have mutations in a protein called nicotinamide nucleotide transhydrogenase (NNT). These mutations caused adrenal cell death and loss of normal steroid production from the adrenal glands. Consequently, and as NNT seems to be directly involved in adrenal cell death, we hypothesise that this protein may be an important regulator of ACC growth. We will test this hypothesis with a number of laboratory techniques at the Institute of Biomedical Research at the University of Birmingham. First, we will inactivate NNT in ACC cells and examine how this affects growth and death rates compared to cells with normal NNT activity, as well as the ability of the cells to produce steroid hormones. Furthermore, after relevant training at the University of Muni ch, I will implant ACC cells (with and without NNT inactivation) under the skin of laboratory mice and monitor tumour growth over 2 months. These studies will show whether NNT inactivation is effective at reducing tumour growth and will provide models to be used for future drug development.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Investigation into the role of rho kinase in the survival of chronic myeloid leukaemia cells.
Funder: Wellcome Trust

Abstract: Chronic myeloid leukaemia (CML) is a blood cancer. Current treatment is not curative and a proportion of patients will die from it. One of the mechanisms behind CML resistance to current therapies is the presence of a population of cells, leukaemic stem cells (LSC) that are insensitive to treatment and have the potential to cause disease relapse. Professor Holyoake's group has an established reputation in studying the mechanisms of LSC resistance and in developing new approaches to kill th em. Maintenance of cellular structure is critical for cell survival and in this project we will investigate the role of the rho kinase (ROCK) pathway involved in maintaining the structure and shape of the cell in the persistence of this LSC population. We aim to clarify whether targeting this pathway alone, or in combination with current treatment will cause additional kill of cancer cells. The research will be carried out on cells from CML patients and mice. This will help identify new potentially curative treatment options for CML patients. It is also probable that some of the mechanisms underlying LSC survival in CML are present in other forms of cancers, so this research might also help develop new treatments for other patients.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Understanding & exploiting 5T4 modulation of CXCL12 chemokine and/or Wnt signalling for treatment of ovarian cancers.
Funder: Wellcome Trust

Abstract: Studying 5T4, a protein found on the surface of up to 70% ovarian cancer cells and particularly in advanced ovarian cancers but not in normal ovary, may hold interesting insights as to how ovarian cancer spreads. In our initial studies we have found that 5T4 is crucial to the movement of leukaemia and lung cancer cells towards the chemical signals CXCL12 and Wnt5a. Through the study of ovarian cancer cells grown outside the body and specimens of ovarian cancers collected from patients under going cancer surgery we will be able to establish whether 5T4 is essential to the response of ovarian cancer cells to directional signals in all types of ovarian cancer and at all stages of the disease. By testing whether using specially developed antibodies (proteins which target and mark or kill cells which are foreign) to block the action of 5T4 and/or drugs which target the ways that 5T4 controls cell movement actually stops spread of cancer cells grown outside the body and in mouse models of ovarian cancer we will build up evidence to support whether or not such drugs may work in humans


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: The Development of First Time in Human (FTIH), Orally Bioavailable, Small Molecule Tankyrase Inhibitors for the Treatment of Cancer.
Funder: Wellcome Trust

Abstract: Every year 1.5 million cases of colorectal cancer (CRC-cancers of the large intestine) are diagnosed. More than half of these patients die within five years, suggesting that an improvement in the way this disease is treated is much overdue. One of the common DNA mutations found in CRC is in a gene known as APC. Mutations in APC drive a molecular process, Wnt signalling, that causes cells to divide uncontrollably and ultimately causes cancer. Although the relationship between APC mutation, Wnt signalling and cancer has been known for some time, until now it has not been possible to specifically kill cancer cells with APC mutations. In this application, a team from the Institute of Cancer Research (ICR) are proposing to develop drugs that target APC mutant cancer cells by suppressing Wnt signalling. Their approach has been to develop drugs that inhibit a protein known as tankyrase. Already the ICR team has developed early-stage drugs. In this application the ICR team are requesting financial support to: (i) complete the later stages of the drug development process and, (ii) carry out the first clinical trial that will assess whether these drugs work in patients.


Research activity codes: 5.1 PHARMACEUTICALS;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Molecular pharmacology of targeted therapy and drug resistance: HSP90 inhibitors.
Funder: Wellcome Trust

Abstract: Heat shock protein 90 (HSP90) is a chaperone molecule responsible for the successful functioning of proteins in cells. Cancer cells produce abnormal proteins (oncoproteins) and they are therefore very dependent on HSP90 to manage cell stress. Hence HSP90 is a potential drug target for many different types of cancer. Drugs that inhibit HSP90 have already been tested in early stage clinical trials and show promise but eventual drug resistance is likely. We propose to further investigate the different components of the pathways involving HSP90 in the response of cancer cells to HSP90 inhibition. We will focus on the molecules involved in the breakdown and removal of oncoproteins from the cell after HSP90 is inhibited. Our aim is to discover lab markers to identify which patients will respond to drug treatment with HSP90 inhibitors and also to identify why patients may become resistant to drug treatment. The research may also identify new drug targets for combination therapy.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Adhesion receptor and matrix metalloproteinase crosstalk: molecular mechanismsand impact on tumour cell invasion
Funder: Wellcome Trust

Abstract: Inappropriate expression or function of adhesion receptors and matrix-degrading proteases has a profound effect on cancer pathogenesis. Consequently, adhesion receptors and matrix metalloproteinases (MMPs) are appealing therapeutic targets. However crosstalk exists between these transmembrane proteins that impacts receptor trafficking and tumour cell invasion and these mechanisms are investigated in this proposal. Expression ofthe adhesion receptor avb6 integrin and MT1-MMP drives invasion of a range of different carcinomas and correlates with patient survival. However, our preliminary data suggest that a complex interplay exists between avb6 integrinand MT1-MMP and that this, at least in part, involves the heparan sulphate proteoglycan syndecan-4 (Syn-4). To effectively exploit adhesion receptors andMMPs therapeutically, it is essential that we understand the dynamic integration of their intracellular trafficking and signalling networks and howthis contributes to tumour cell invasion. We will use gene editing, live-cell imaging and photoactivation, in addition to biochemical and proteomic strategies, to determine how aVb6, MT1-MMP and Syn-4 trafficking and signalling are co-ordinated spatially and temporally in invading carcinoma cells. Delineating how avb6, Syn-4 and MT1-MMP are functionally integrated, during tumour cell invasion, will improve our understanding of cancer metastasis and could provide insight into novel targets for therapeutic intervention.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: An investigation into the role of ATPase Inhibitory Factor 1 in pancreatic cancer
Funder: Wellcome Trust

Abstract: This is a basic research project investigating the role of IF1 (ATP synthase inhibitory factor 1) in bioenergetics and adaptability of pancreatic cancer cells. In hypoxic or anoxic conditions, when the respiratory electron chain cannot work effectively, mitochondrial ATP synthase can switch from an ATP producer to an ATP consumer. The reverse action of ATP synthase is unfavourable for cell types that need to survive in hypoxic conditions. Among those cell types are pancreatic ductal adenocarcinoma (PDAC) cells. IF1 is a small naturally-occurring protein that inhibits the reverse (ATP-consuming) activity of ATP synthase. High expression levels of IF1 are expected to increase cell survival in hypoxic conditions. IF1 expression and its effects on cellular bioenergetics have not been characterised in PDAC. In addition to its primary function in adjusting cellular bioenergetics IF1 has been shown toregulate apoptosis. PDAC is a poorly vascularized cancer and it is therefore reasonable to hypothesise that IF1 should be abundantly expressed in PDAC cells and play a prominent role in their bioenergetics. Furthermore, highly expressed IF1 couldplay an important role in metabolic adaptation and resistance to apoptosis of PDAC cells. The key goals of the project are to test these hypotheses.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Prostate Cancer and PSA: Examining the role of mediation in the associations of individual characteristics with prostate specific antigen (PSA) and prostate cancer.
Funder: Wellcome Trust

Abstract: The objectives of this research are to: 1) Identify variables that have a large body of evidence indicating an association with both prostate cancer andPSA; 2) Perform a systematic review of selected variables, PSA and risk of prostate cancer; 3) Assess and use multi-parameter evidence synthesis of published data to determine the relationships between the variables, PSA and risk of prostate cancer; 4) Assess the current statistical methods to enable the calculation of an individual variables direct effect on PSA independent ofthe indirect effect on PSA through prostate cancer, then use the most appropriate methods to estimate these effects from collaborative data; 5) Update the multi-parameter evidence synthesis using the estimates from the data analysis; 6) If time, develop a model for screening using PSA that uses the relationship between the identified variables and prostate cancer risk as a prior, with the adjusted PSA as a likelihood ratio for having prostate cancer.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS