NIHRDataInsights/HRCSData huggingface dataset:
Title: A randomised phase 2 trial of IM versus HCQ/IM for patients with CML in MCyR with residual disease by Q-PCR
Funder: Medical Research Council

Abstract: Imatinib mesylate (IM) is standard therapy for CML. The main limitations of IM and second generation tyrosine kinase inhibitors (TKI) are development of resistance and instrinsic refractoriness of CML stem cells to these agents. Therefore, new therapeutic approaches that more effectively target CML stem cells and prevent the outgrowth of TKI-resistant cells are required. Our preliminary data (JCI in press) lead us to believe that autophagy is a major cause of TKI-resistance in CML stem cells. We have shown that IM induces autophagy in BCR/ABL+ cells, including primary CML stem cells. Suppression of autophagy in BCR/ABL+ cells using pharmcological inhibitors or siRNA-mediated knockdown of essential autophagy genes enhances cell death induced by IM in primary CML cells, demonstrating that induction of autophagy has a pro-survival effect. Critically, the combination of TKI with inhibitors of autophagy (chloroquine and bafilomycin A1) results in near complete elimination of phenotypically and functionally defined CML stem cells, including CFC and LTC-IC. Together, these findings suggest that autophagy inhibitors will enhance the therapeutic effects of TKI in the treatment of CML. Hydroxychloroquine (HCQ), a less toxic derivative of chloroquine, has been widely used in rheumatology over many years, often at the same time as multiple other drugs. IM now has a 10 year clinical experience and is well tolerated. Here we propose to lead a randomised phase 2 trial with a safety run-in across 3 UK centres in which we will investigate the safety of combining IM with HCQ and compare the efficacy of the combination vesus IM alone in reducing levels of residual disease in CML chronic phase patients who have achieved MCyR after 12 months IM monotherapy but have residual disease as shown by Q-PCR. Patients will be recruited over 24 months, combination treatment will be for 12 months with a further 12 months follow-up.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES;6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Bile acid modification by the human gut microbiota and its role in pathogenesis of colorectal cancer
Funder: Medical Research Council

Abstract: CRC is the third most common malignancy worldwide and it is estimated that more than 100 new cases are diagnosed daily in the UK. The incidence of this disease worldwide has risen from ~500,000 new cases in 1975 to over a million new cases in 2002. Acquisition and pathogenesis of sporadic CRC is complex and multifactorial. While diet has consistently been associated with an increased risk of CRC, the underlying mechanisns which result in genetic damage and carcinogenesis are poorly understood. There is increasing evidence that the indigenous gut microbial population is a significant factor in the pathogenesis of CRC, and that this community mediates the effects of diet on colonic health. In particular microbial bile acid modification is emerging as a key activity through which the gut microbial population and dietary factors interact to initiate CRC or enhance its progression. The products of microbial bile acid metabolism have been proposed to act as carcinogens and activate pro-inflammatory regulators such as NF-kB and COX-2 which result in the inhibition of apoptosis and the survival of malignant cells. Recent studies have also indicated that the capacity for bile acid modification may vary between the gut microbial populations of different individuals, and if so this could relate to overall risk of CRC acquisition. The overall aim of this project is to identify any relationship between the capacity for bile acid modification in the human gut microbiota and acquisition of colorectal cancer. The capacity for bile acid metabolism in the gut microbiomes of healthy individuals, and those with CRC and pre-cancerous polyps will be determined and compared. The contribution of microbial bile salt hydrolase (BSH) upon activation of key host encoded genes (NF-kB and COX-2) involved in inflammation, inhibition of apoptosis, and acquisition of CRC will be established. Ultimately this will clarify the relationship between microbial bile acid metabolism and CRC, and elucidate underlying mechanisms of disease.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Elucidating the role of JAM-B in breast cancer and angiogenesis
Funder: Medical Research Council

Abstract: Down Syndrome (DS) is a genetic disorder caused by full or partial trisomy of chromosome 21. It presents with many clinical phenotypes including a reduced incidence of solid tumours, in particular breast cancer. This phenotype is thought to occur as a consequence of chromosome 21 ?gene-dosage? effects and suppression of angiogenesis. We will use the transchromosomic (Tc1) mouse model of DS, which expresses 81% of human chromosome 21 (Hsa21) genes, to understand why individuals with DS have a reduced incidence of breast cancer. We will focus on the gene-dosage effect of the JAM-B gene, located on Hsa21. We have compelling preliminary showing that JAM-B, an endothelial cell-specific gene, when overexpressed, is responsible for the inhibition of tumour angiogenesis. We will breed Tc1 mice with JAM-B transgenic mice to generate mice that have 2 copies of JAM-B (Tc1/JAM-B+/-). Using both Tc1 and Tc1/JAM-B+/- mice we will i) examine the gene-dosage effect of JAM-B on breast cancer and angiogenesis and ii) understand the mechanism of action of JAM-B in the regulation of angiogenesis.By using an interdisciplinary approach combining angiogenesis assays with the Tc1 DS model we will identify the gene-dosage effect of JAM-B on breast cancer and tumour angiogenesis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Molecular and pharmacological validation of Cathepsin S as a novel target in cancer treatment
Funder: Medical Research Council

Abstract: The cysteine protease, cathepsin s, has been implicated in the promotion of the invasive and angiogenic phenotypes of aggressive tumours. Normally found in lysosomes of cells with a restricted tissue expression, cathepsin S has been implicated in the progression of aggressive metastatic tumours. Immunohisto- and biochemical characterization of tumour biopsies has revealed expression and secretion of CatS, where it is thought to mediate remodelling of the extracellular matrix, promoting growth and spread of the tumour and tumour-associated cells. The aim of this work is to validate the targeting of cathepsin S as an anti-tumour therapeutic target; and to evaluate therapeutic inhibition of the enzyme in models of primary tumours and metastases. This investigation will involve the application of in vivo synengenic murine studies to examine both tumour development with stratified cathespin S depletion and the evaluation of a novel experimental therapeutic towards cathepsin S.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Induction and repair of UVAI (340-400nm) induced cyclobutane dimers (CPD) in human skin in vivo and their biological con
Funder: Medical Research Council

Abstract: Although over 95% of ultraviolet radiation (UVR: wavelengths ~295-400nm) in sunlight is UVA (320-400nm), research has focussed on the smaller UVB (280-320nm) component because it has been thought to be the main cause of skin cancer. We plan to explore the health effects of UVAI radiation (340-400nm) in vivo in humans, in light of new in vitro evidence that UVAI may be more carcinogenic than previously thought. In the skin, absorption of UVB from sunlight creates cyclobutane pyrimidine dimers (CPD) in DNA. Unrepaired CPDs induce UVB signature mutations (C?T and CC?TT), whose presence in skin cancers has been presumed as key evidence for the role of UVB in inducing skin cancer. CPDs are also important in skin inflammation, immunomodulation and photoageing. It has been thought that CPD only result from absorption of UV by DNA, which readily occurs with UVB and UVAII (320-340nm) but weakly with UVAI which exerts effects indirectly by generating reactive oxygen species (ROS). Unexpected recent in vitro data show that CPD are also induced by UVAI, by an unexplained mechanism. This implies that the UVAI component of sunlight may be more carcinogenic than previously thought. UVAI makes up 75% of the UVR in sunshine, almost all the radiation from sunbeds, and high dose UVAI phototherapy is being increasingly used to treat skin diseases. Thus, the safety of UVAI in human skin is a critical question in the effort to reduce the incidence of skin cancer. We will determine the role of UVAI in the formation of CPD in humans in vivo. We will take skin biopsies after UVAI exposure (acute and repeated), from human volunteers and patients undergoing UVAI phototherapy. CPD repair kinetics will be examined by quantitative immunostaining and sensitive HPLC techniques. Downstream effects of CPD in UVAI-exposed skin will be assessed at the gene and gene product level, with mRNA analyses (DNA microarrays, PCR and in situ hybridization) and quantitative immunostaining. The fellow will learn laboratory and data analysis techniques in experimental photobiology, develop an understanding of environmental photobiology, and ethical issues in human research. The candidate will get a full training in clinical photodermatology and skin photobiology. The results of the project will allow the modification of public health strategies for skin cancer so that the appropriate component of solar radiation is protected against. They will also enable dermatologists to understand the long term safety of UVAI phototherapy and modify treatment protocols accordingly.


Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CANCER AND NEOPLASMS
Title: Applications of probabilistic machine learning to medical biostatistics
Funder: Medical Research Council

Abstract: Biomedical research accumulates huge volumes of scientific data. Because of this, it is necessary to develop computational and statistical methods that can effectively extract important information from these data. These data-sets can present a number of challenges. The underlying biological systems are often highly complex, leading to rich structure in the data. They are typically also noisy, both as the result of measurement imprecision and also any biological variation that may be intrinsic to the system studied. The data-sets are often also large, particularly from high-throughput technologies such as microarrays that allow simultaneous measurement of whole genomes. This work will develop novel non-parametric Bayesian methods to address key questions in three areas of medical biostatistics. Firstly, the integration of multiple sources of data into combined biomarker discovery/outcome prediction models. Secondly, the use of Bayesian model averaging techniques to develop more effective data models for clustering of gene expression data. Thirdly, the creation of hierarchical data models that can simultaneously cluster, identify biomarkers and make outcome predictions. Non-parametric Bayesian methods represent a powerful way to address these challenges. Because they are highly flexible, they can accurately model the sort of complex structure often found in biomedical data-sets and can select in a principled way the most appropriate model structure, leading directly to superior data modelling results. Their Bayesian nature also makes them suitable for modelling uncertainty in the data and for using all available sources of information for a given analysis. The particular families of non-parametric models I‘ll be using are Gaussian Process and Dirichlet Process models, both of which are on the cutting-edge of current machine learning research. The medical focus of this work will be cancer, with a particular early focus on data-sets investigating breast cancer, myeloma, ovarian carcinogenesis and basal cell carcinoma. My collaborators and I will extend this work both as new data-sets become available, and also as we identify promising analysis results to follow up, for example in the design of new experiments or clinical trials. This work will produce original research in probabilistic machine learning and I will develop these innovations into robust software tools so that the broader scientific community can benefit fully from this work.


Research activity codes: 8.4 RESEARCH DESIGN AND METHODOLOGIES (HEALTH SERVICES);2.5 RESEARCH DESIGN AND METHODOLOGIES (AETIOLOGY)
Health categories: CANCER AND NEOPLASMS
Title: Functional genomic identification of predictive biomarkers of everolimus sensitivity and of new molecular targets in ren
Funder: Medical Research Council

Abstract: Background: The mTOR (mammalian Target Of Rapamycin) inhibitor everolimus is active in renal cell carcinoma (RCC) but intrinsic and acquired drug resistance limits efficacy. Everolimus has direct cytostatic effects on RCC cells and anti-angiogenic activity through the suppression of hypoxia inducible factor 1 (HIF1 ) and its target VEGF in von-Hippel-Lindau (VHL)-gene deficient RCCs, and by inhibiting mTOR in endothelial cells. Mechanisms of everolimus resistance are poorly understood and there are no reliable predictive biomarkers of response. Aims: Whole genome siRNA screens will be applied to RCC cell lines to identify genes that mediate resistance to the cytostatic effect of everolimus, the hypoxic environment generated by its anti-angiogenic activity, and to the suppression of the HIF1 -VEGF pathway by mTOR inhibition. These results and their integration with transcriptomic and genomic profiles of pre- and post-treatment tumour samples from a clinical trial of everolimus in patients with RCC will identify: 1. Clinically relevant resistance mechanisms 2. Predictors of everolimus sensitivity and resistance 3. Therapeutic targets leading to synthetic lethality in VHL deficient RCC cell lines Design and methodology: A siRNA screen has already been performed in a VHL deficient RCC cell line and identified novel mediators of everolimus resistance and sensitivity. Further immunostaining of this screen for carbonic anhydrase IX as a marker for HIF1 activity will identify genes that contribute to in vivo resistance by rescuing HIF1 activity and -target gene expression in the presence of everolimus. A second siRNA screen will be performed to reveal how RCC cells can develop resistance to hypoxic conditions. Resistance mechanisms will be further characterized in vitro and by systems biology approaches. Screening results will be compared with mRNA expression, copy number variation and whole genome exon capture sequencing datasets obtained from pre- and post- treatment RCC tumour samples to identify which genes are relevant to resistance in patients. Candidate predictive biomarkers will be assessed in a validation cohort. Genes causing synthetic lethality in the VHL-null background when repressed will be identified in isogenic VHL-wt and VHL-null cell lines. Scientific and clinical opportunities: This approach should lead to the identification of a predictive biomarker of everolimus response in RCC. It should simultaneously define molecular mechanisms of resistance and potential targets to facilitate the development of new therapeutic strategies. These strategies could reduce the health economic burden associated with therapeutic resistance and improve outcomes in RCC by targeting treatment to patients with molecularly pre-defined drug sensitive disease.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Regulation of cancer cell migration by voltage-gated sodium channels
Funder: Medical Research Council

Abstract: The long-term goal of this research is to elucidate the functional role of voltage-gated Na+ channels (VGSCs) in breast cancer (BCa) metastasis. VGSCs exist as membrane complexes containing a pore-forming subunit with one or two subunits. Through the 1 subunit, which is an immunoglobulin (Ig) superfamily cell adhesion molecule, VGSCs regulate migration of neurones in the developing CNS in vivo. Recent work, largely restricted to in vitro models, has shown that VGSC and 1 subunits are expressed in metastatic BCa cells, and regulate cell behaviours associated with metastasis, including adhesion, migration and invasion. This proposal aims to test the hypothesis that VGSCs control cellular migration and invasion in metastatic BCa, by a mechanism that recapitulates neuronal signalling. In addition to using in vitro cell lines, I will develop an in vivo approach, using an established animal model and human biopsy material to characterise the expression and activity of VGSCs in metastatic BCa. I propose three specific aims In Aim 1, I will investigate the mechanism of 1-mediated signalling in regulating the adhesion and migration of BCa cells. Specifically, I will test whether mechanism(s) underlying 1-mediated adhesion and migration in BCa cells may be analogous to those operating in neurones, using a combination of functional in vitro adhesion, migration and invasion assays, Western blotting and confocal immunocytochemistry. In Aim 2, I will investigate whether VGSC expression affects tumour formation and/or metastasis in nude mice in vivo. I will then test whether the VGSC-inhibiting drug phenytoin affects the tumour formation and/or metastasis. In Aim 3, I will determine whether VGSC expression and activity correlates with metastatic potential in human BCa tumour biopsies, using a combination of tissue microarrays, immunohistochemistry, realtime PCR, functional assays, Western blotting, confocal microscopy and patch clamp recording. The study will characterise VGSCs as new potential diagnostic and therapeutic targets in BCa, which is the most commonly diagnosed cancer in women, and the second-leading cause of cancer-related deaths. In particular, the study focuses on the process of metastasis, which is of major clinical importance, since it is the main cause of BCa mortality. Given that VGSCs are well established as clinical targets in the treatment of other diseases, such as epilepsy and pain, based on this work, it is possible that VGSC-modulating drugs already in use may also be effective in BCa therapy.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Preventing TAB1-mediated p38 activation during myocardial infarction
Funder: Medical Research Council

Abstract: The activation of 38alpha mitogen-activated protein kinase (p38alpha) during myocardial ischaemia aggravates lethal injury. However, under other circumstances activation of this kinase can protect the heart. During myocardial ischaemia the activation of p38alpha occurs through an unusual mechanism involving a scaffold protein known as TAB1 that causes p38alpha to autophosphorylate its activation loop. The purpose of this project is to characterise the molecular basis of the interaction between p38alpha and TAB1 in order to disrupt it. The interface residues on p38alpha and TAB1 will be mapped by NMR chemical shift perturbation and cross-saturation transfer techniques and then confirmed by mutagenesis analysis. The TAB1-induced 3 dimensional rearrangement of p38alpha will also be analysed. This information will be used to design peptides and small molecules to disrupt the TAB1-p38alpha interaction in physiological systems Such reagents maybe of considerable value since they could prevent the detrimental, but not the beneficial, activation of p38 and thereby perhaps overcome the toxicity seen to date in clinical trials of inhibitors of p38 catalytic activity.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Developing a novel therapy, combining RIT with conventional therapy, for treatment of advanced colorectal cancer
Funder: Medical Research Council

Abstract: Colorectal cancer is the third most common cancer in the UK ( 38,000 new cases/annum), with 50% mortality rates. Radioimmunotherapy (RIT), the use of antibodies for sustained targeting of therapeutic radionuclides to the tumour, increases specificity of treatment and reduces systemic toxicity. Using antibodies that bind to carcinoembryonicantigen (CEA), overexpressed in colorectal tumours, we have shown RIT responses in pre-clinical and clinical studies. However, tumours have a tendency to regrow, because of non-uniform radiation dose delivery to cancer cells, and their differential sensitivity to radioactivity. This is aggravated by both the heterogeneous microenvironment and mutated genotype of the cells, which affect how tumours respond to ionising radiation. This treatment failure necessitates a combination therapy to significantly enhance RIT radiation damage. We previously combined RIT with vascular disprupting agents clinically, and obtained partial responses in patients refractory to standard treatment. We propose combining a humanised 131I?labeled anti-CEA antibody with a second antibody that also targets colorectal cancer. This antibody enhances sensitivity of tumours to external beam radiation clinically, and significantly augments RIT in our own pre-clinical studies. We plan to optimise timing and dosing schedules for this combined antibody therapy, for easy translation into early phase clinical trial within 3 years


Research activity codes: 5.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Chromosomal Instability in Cancer Pathogenesis and Treatment (MRC Programme 1)
Funder: Medical Research Council

Abstract: Instability in the structure and number of chromosomes is a hallmark of virtually all human epithelial cancers, and is triggered early during their development. What provokes chromosomal instability, and how it fosters cancer pathogenesis, are major unresolved questions central to understanding carcinogenesis. The near-universal occurrence of chromosomal instability in common epithelial malignancies offers important opportunities for devising new approaches to cancer therapy, which remain to be explored. This programme aims: To understand the mechanisms that engender chromosomal instability and define their contribution to epithelial carcinogenesis. In so doing, to develop new approaches for cancer therapy that can be applied in the clinic, exploiting the novel interdisciplinary platforms being developed in the Cambridge Molecular Therapeutics Programme (CMTP). Each future project builds on new discoveries and experimental approaches from the last quinquennium, and represents a progression from mechanistic studies towards their translation to cancer pathogenesis and treatment. We will investigate how cancer-associated mutations in BRCA2 affect the new tumour suppressive functions we have recently discovered, using a range of new fluorescence imaging methods we have established to probe BRCA2 function at single-molecule resolution in vitro and in vivo. We will define the molecular evolution of BRCA2-deficient familial pancreatic cancer using powerful genomic and proteomic approaches in a new murine model, and use it as a test-bed for new treatments, including a first-in-class drug exploiting a new approach (Targeted Synergy) to selectively kill hypoxic tumour cells. We will use the functional genomics platforms now established in our lab to identify new molecular components of the pathways discovered in the last quinquennium that determine the response of cancer cells to agents that inhibit DNA repair or mitosis. Clinical collaborations will test the value of new pathway mediators as prognostic or predictive biomarkers in patients with epithelial cancers.


Research activity codes: 5.1 PHARMACEUTICALS;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS