NIHRDataInsights/HRCSData huggingface dataset:
Title: Elucidating the functional significance of Jagged1 proteolysis in the tumourigenicity and metastasis of prostate cancer epithelial cells
Funder: Cancer Research UK

Abstract: Notch signalling is critical for cell fate decisions, pattern formation and stem cell population maintenance, and its dysregulation has been linked to many different cancers.. Prostate cancer metastasis, disease progression and prognosis have been particularly strongly linked to dysregulation of the Notch1 receptor and one of its ligands, Jagged1. At the molecular level, down-regulation of Jagged1 reduces malignant prostate epithelial cell (PEC) proliferation. This previous research relates to the Jagged1 holoprotein. We and others, however, have demonstrated that the holoprotein can be proteolytically cleaved from the cell surface generating a diffusible form of the ligand (sJag1) and a membrane-associated Jagged1 C-terminal fragment (JCTF), which can be further processed to generate transcriptionally active Jagged1 intracellular domain (JICD). The generation of these Jagged1 proteolytic fragments raises the possibility that they too might be involved in prostate cancer pathogenesis, as sJag1 could conceivably regulate long distance Notch signalling and JICD generation has previously been linked to altered cell signalling and cell transformation. Having demonstrated that sJag1 can promote malignant PEC proliferation and that these cells have the capacity for JICD generation, we intend to elucidate the functional significance of this process in the tumorigenicity and metastasis of PECs and to examine the molecular pathways involved. Furthermore, we intend to provide basic proof of concept that inhibiting Jagged1 proteolysis might represent a possible therapeutic avenue for prostate cancer treatment. We will initially examine the relationship between Jagged1 expression/proteolysis and the malignancy/hormone-sensitivity of a range of PEC lines, including primary cells from benign and malignant prostate tissue. The effect of truncated Jagged1 constructs analogous to its proteolytic fragments on the proliferation, colony formation, migration and invasion of various PECs will then be examined in different microenvironment models. We will then examine how sJag1 influences the proteolysis and subcellular localisation of Notch1 and how our various truncated constructs affect the transcriptional regulation of key proteins involved in Notch signalling, metastasis and the cell cycle. Finally, we will develop methods for the specific inhibition of Jagged1 proteolysis with a view to investigating the effects of such inhibition on the growth parameters of PECs and assessing whether altering Jagged1 proteolysis might be used in the treatment of prostate cancer. The research will primarily serve to elucidate the relevance of Jagged1 proteolysis to the development of prostate cancer and determine how this might be regulated in order to treat the disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Understanding and overcoming resistance to MEK1/2 inhibitors in tumour cells
Funder: Cancer Research UK

Abstract: Background Inhibition of MEK1/2 on the RAS-RAF-MEK1/2-ERK1/2 pathway is a promising anti-cancer strategy. Unlike RAF inhibitors, MEK inhibitors (MEKi) do not cause paradoxical activation of the pathway and so may be used to treat tumours with BRAFMut, RASMut or RTKMut/Amp, though they will be most effective when used in combination with other agents. Recent results indicate that innate resistance to MEKi is apparent, whilst acquired resistance is inevitable. Aims We will define cellular mechanisms of innate and acquired resistance to MEKi to inform new combination strategies. Specifically we will: (i) Identify therapeutic strategies (combination therapies with MEKi) that delay the onset of acquired resistance by maximizing tumour cell responses to primary treatment; (ii) Define the pathways driving acquired resistance to MEKi arising from KRASMut amplification and thereby develop strategies to overcome it, and (iii) Identify novel mechanisms of acquired resistance to MEKi. Methods We will use authenticated human tumour cell lines with defined oncogenic mutations. (i) We will investigate the effects of combining MEKi with two other classes of drug - RAF inhibitors or BH3 mimetics - on cell death and the development of acquired resistance. (ii) To investigate acquired resistance we will use derivatives of these cell lines that we have rendered resistant to MEKi in vitro through continuous culture in the presence of AZD6244 or PD184352. This well-recognized method has led the way in defining clinically-relevant mechanisms of acquired resistance to targeted therapeutics such as gefitinib and imatinib. We have recently shown that acquired resistance to MEKi can arise by amplification of KRASMut. We will determine how amplified KRASMut drives acquired resistance to MEKi and develop strategies to overcome it. (iii) Amplification of either BRAFMut or KRASMut is a common mechanism of acquired resistance to MEKi. Nonetheless, isogenic derivatives of tumour cell lines lacking KRASMut still develop MEKi resistance by alternate means. We will use these and other isogenic lines in which specific oncogenic alleles or downstream effectors have been deleted by homologous recombination to define new mechanisms of acquired resistance to MEKi. How will the results be used The results of this study will provide valuable new information on how tumour cells respond and adapt to new, targeted therapeutics active on the RAF-MEK1/2-ERK1/2 pathway. This will (i) help to develop the clinical use and enhance the efficacy of these agents, (ii) anticipate new mechanisms of acquired resistance and (iii) identify strategies to overcome them.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: Characterisation and functional analysis of the tumour-associated macrophage in the progression of Intrahepatic Cholangiocarcinoma
Funder: Cancer Research UK

Abstract: Background Cholangiocarcinoma is an aggressive tumour of the bile duct epithelium with a characteristic dense stroma. This stroma impairs delivery of chemotherapy making the tumour resistant to treatment. A dense stroma co-evolves along with the cancerous epithelium and supplies growth signals, anchorage and promotes development and expansion of the cancer. One key cell type in the stroma is the macrophage. Increasingly the role of macrophages in cancer establishment and progression is seen as important. In human cholangiocarcinoma, so called “Alternatively Activated” macrophages positively correlate with poor, disease-free survival; however it is not known how macrophages confer this disease phenotype. Aims To characterise the role of the macrophage in the formation and progression of intrahepatic cholangiocarcinoma. We are interested in the specific signals that the macrophages make in the tumour and whether by blocking these signals we can prevent tumour formation and progression. How the results of this research will be used This study will inform us whether macrophages are important in the establishment and survival of cholangiocarcinoma, and whether macrophage derived signals in the tumour could be used as targets for novel therapeutics.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Colorectal adenomas, Barretts oesophagus, colitis-associated cancer
Funder: Cancer Research UK

Abstract: We have evolved methods of measuring the extent of clonal expansion in human tissues using mtDNA mutations, coupled with measurements of the rate of clonal expansion using the methylation status of non-expressed genes and mathematical modelling. We have perfected genetic dependency analysis to examine clonal expansion and wish to combine these methods with assessment of mutations in critical tumour suppressor and oncogenes to understand the genetic mechanisms underlying clonal evolution in pre-neoplastic conditions in gastrointestinal epithelia. We wish to study the genetic factors which control the rate of clonal expansion in sporadic colonic adenomas, in Barrett’s oesophagus and in colitis-associated dysplasia. In Barrett’s oesophagus we will also use these methods to search for the origin of Barrett’s epithelium and examine the efficacy of mucosal ablation therapy on the persistence of mutated clones. In inflammatory bowel disease (IBD) we will investigate the mechanism of spread of mutated cells in IBD and examine the genetic and epigenetic mutation burden of a cohort of human colitis-associated tumours. We also intend to look for pro-tumourigenic epigenetic fields, particularly of p16, in IBD-neoplasia colectomy specimens to assess the use of genomic changes in predicting cancer risk in IBD and to establish more appropriate markers for the detection of pre-neoplasia. We believe these studies go some way towards detecting the clonal expansion of stem cells in pre-neoplastic lesions in vivo in man. We consider that these studies will enable us to identify and characterise pre-tumour clones in human pre-neoplastic conditions, and to study the mechanism of expansion of these mutated clones with a view to the design of rational biomarkers of an individual patient’s risk of disease progression.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS
Title: Histone Demethylase Target Validation in Cancer
Funder: Cancer Research UK

Abstract: Epigenetic regulators control numerous processes involved in cellular transformation, including transcription, DNA repair and mitosis. Enzymes that modify the methylation status of histones have been shown to be involved in regulating several transcription factors and display aberrant expression in cancer, implicating a role for these proteins in tumour progression. Research teams from the Northern Institute for Cancer Research (NICR), Newcastle University and the Institute of Cancer Research (ICR), Sutton, Surrey, have identified specific histone modifying enzymes as potentially druggable therapeutic targets in specific types of cancer. However, the current level of target validation is not yet sufficient to warrant the investment required for a full drug discovery project at the CR-UK Cancer Therapeutics Unit at the ICR. This project builds on an evolving collaboration between these two research centres and the unmet clinical need for more effective, less toxic treatment for patients and aims to fully validate specific products of genes encoding histone modifying enzymes as therapeutic targets in cancer.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/055: A Randomised phase II trial of Olaparib maintenance versus placebo monotherapy in patients with non-small cell lung cancer
Funder: Cancer Research UK

Abstract: Background: Non-small cell lung cancer (NSCLC) is the most common cause of cancer related death, but remains under-researched. NSCLC is a heterogeneous cancer. Successful targeting morphological or molecularly defined subtypes has led to a new paradigm based on personalizing therapy. Somatic genetic alterations in NSCLC including loss of BRCA1 expression, are associated with defective DNA and exquisite sensitivity to poly ADP ribose polymerase (PARP) inhibition. BRCA1 expression correlates inversely with platinum sensitivity, however administration is limited by toxicity. We hypothesize that DNA damage sensitive NSCLCs harbour somatic alterations in BRCA1 and other DNA repair proteins, and propose that PARP inhibition with olaparib will selectively induce synthetic lethality leading to improved disease control. Aims: The overall aim is to conduct a randomized phase II trial of switch maintenance therapy with olaparib in patients with DNA damage sensitive advanced NSCLC. Primary Objectives: 1) To establish the anti-tumour activity of maintenance olaparib as measured by PFS in DNA damage sensitive NSCLC. Secondary Objectives: 1)To determine the toxicity profile of maintenance 2)To determine the feasibility of use of maintenance 3)To collect tumour and blood samples for future translational work including investigating BRACA1 expression 4) To determine other anti-tumour activity as measured by response, tumour volume reduction and overall survival. Methods: Main inclusion Criteria 1. Histological diagnosis; 2. stage IIIB/IV NSCLC; 3. eligible to receive standard platinum doublet based chemotherapy; 4. age = 18; 5.Chemonaive; 6. willing to consent to provide tissue for translational research; 7. measurable lesions by RECIST; 8. response (partial or complete) to induction chemotherapy; 9. Informed consent; 10. Evidence of radiological response (partial or complete) to induction chemotherapy Following 4-6 cycles of induction chemotherapy, patients exhibiting a radiological response (partial or complete) measured by computerized tomography by RECIST will be randomised 1:1 to receive olaparib or placebo. Based on a hazard ratio of 0.65 (90% power, 1 sided type I error of 0.2), 114 patients will be randomized. The study will be double blinded. Patients will receive treatment until disease progression. They will be monitored by CT scan every two cycles until disease progression, whereupon they will be monitored in accordance with local imaging procedures How the results of this research will be used: If this phase II trial is positive, this will lead to initiation of a pivotal phase III trial to evaluate PARP inhibitor switch maintenance in NSCLC.


Research activity codes: 6.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: CRUK/11/057: A randomised phase 2 trial investigating the additional benefit of hydroxychloroquine to short course radiotherapy in patients aged 70 years and older with high grade gliomas. A sub study investigating the role of 18 F FDG PET CT in addition to MRI in detecting tumour response
Funder: Cancer Research UK

Abstract: Background: High Grade Gliomas (HGG) remain amongst the most difficult tumours to treat with a median survival even with optimal treatments a little over 1 year. It is becoming more common in people over the age of 70. Studies that have defined current chemoradiation regimes have not included this patient group and there is no standard management. Accepted practice in the UK is short course radiotherapy using hypofractionated regimes. The additional benefit of temozolomide is less clear. A non toxic treatment which is well tolerated and improves the outcome of short-course radiotherapy would be practice changing. Inhibition of autophagy with the anti-malarial drugs chloroquine and hydroxychloroquine may make tumours more sensitive to chemo/radiotherapy. In HGG, three small trials within the same institution suggest that the addition of chloroquine improves survival in patients who receive standard radical treatment. Hydroxychloroquine has a better long term toxicity profile and is the most common autophagy inhibitor in clinical studies. Radiological monitoring is important in HGG management. T1–weighted MRI is the investigation of choice,but following radiotherapy, interpreting it may be complicated by pseudoprogression (PsPD). This can be improved by co-registering MRI with PET acquiring metabolic information as well. Aims and Objectives: • To investigate the activity of Hydroxychloroquine as an adjuvant treatment to radiotherapy in patients aged 70yrs and older with HGG. • To investigate the incremental diagnostic accuracy of adding 18 F FDG PET CT to MRI in the HCQ + radiotherapy arm. • To study early changes in SUV as a potential imaging biomarker for autophagy modulation. Methods: Eligible patients aged 70 yrs or older will be consented to receive standard short course radiotherapy (30Gy, 5Gy/d, 6 fractions) Patients will be randomised to recieve the experimental component, Hydroxychloroquine which will commence on day 14 post surgery (200mg bd p.o.) until evidence of radiological/ clinical progression. 10 patients will be further consented to have additional 18 F FDG PET CT scans, to be done before surgery, after 2 fractions, after 5 fractions and at 12 weeks. Standard MRI will be done before surgery and at 12 weeks. How will the results be used? If the data from this trial supports the principle that autophagy represents an effective target in radiosensitisation in glioma then an important outcome will be the design of a phase 3 study to compare this treatment to standard management.This trial will also contribute to developing an imaging biomarker of autophagy modulation.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.5 RADIOTHERAPY AND OTHER NON-INVASIVE THERAPIES;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS
Title: A novel anti-metastatic chemokine binding protein
Funder: Cancer Research UK

Abstract: Malignant melanoma is the most lethal form of skin cancer claiming over 2000 patients lives per year in the UK. It is the distant metastases that are lethal, not the primary tumour, and once the cancer has spread to the liver, lungs or brain prognosis is very poor. Melanomas in the skin spread first to the lymphatic system, then the lymph nodes, and from there through the blood stream to distant sites. To do so the tumours evolve mechanisms to recognise their target cell type, the endothelial cells of the lymphatic and blood capillaries. They do this by expressing receptors on their surface that they use to recognise secreted chemokines from specific endothelial cells. Two of the most powerful endothelial secreted chemokines for melanoma cells are CCL21, expressed by lymphatic endothelial cells, and CXCL12 expressed by endothelial cells of the lung, liver, brain, etc – the sites that melanomas seed to. Antibodies to CCL21 can prevent growth of melanoma cells toward lymphatic endothelial cells and blocking the receptor for CXCL12 in cancer cells is being developed as a therapy for metastatic melanoma. We have developed a protein that contains a high affinity binding domain to CCL21, and which inhibits CCL21 mediated migration of tumour cells into lymphatics. We have now identified that this protein, termed Chemotrap-1 also binds CXCL12, (but not CCL2, CCL11, CCL19 or CCL20), and blocks metastasis of melanoma cells that express CCR7 and CXCR4, the receptors for both CCL21 and CXCL12, respectively. This project is designed to determine the affinity, and specificity of chemotrap to other chemokines, improve the affinity by site directed mutagenesis, determine the half life of chemotrap in animals and its efficacy in animal models of melanoma metastasis. At the end of the project, if successful it should lead to a compound ready to move into the clinical arena through licensing to biotech or pharmaceutical companies.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: CANCER AND NEOPLASMS
Title: Translational research in individuals with genetic predisposition to cancer: the prostate cancer genetic predisposition programme
Funder: Cancer Research UK

Abstract: Background Prostate cancer (PrCa) is the commonest cancer in men in the UK; there are 37,051 new cases per annum, 10 168 deaths and a lifetime risk of 1 in 9 by age 80 years (Cancer Research UK Statistics). There is evidence from twin and epidemiological studies of genetic predisposition to PrCa and mathematical modelling suggests that this is due to a combination of common (over 5% allele frequency) PrCa susceptibility variants with slightly increased risks, less common (allele frequency of 3-5%) with higher relative risks (RRs; we predict about 2-3 fold) and rarer variants of less than 3% (many will be less than 1%) with very high RRs of about 5-10 fold or higher. The common variants can act together to confer substantial risks to those with a high risk genetic profile and as they are common they are important for population risk stratification. The rarer variants are important to the individual and their family as they may be targets for screening of high risk groups and drug development. Some of these are already known to be associated with aggressive PrCa and can be used to target therapy, and so will be important in the care of PrCa patients. Aims 1. To identify individuals with an increased risk of PrCa due to a genetic predisposition 2. To translate these findings into clinical practice Methods We have created and lead several large consortia which bring together many researchers with thousands of samples worldwide to conduct large genetic studies in this disease. The consortia consist of (i) over 50 groups internationally with access to over 100 000 samples to find new genetic variants (the PRACTICAL consortium); (ii) 44 groups internationally to determine how men with genetic susceptibility to PrCa should be screened (the IMPACT study); and (iii) a clinical consortium to determine how genetic susceptibility impacts on PrCa care, for example by targeting treatment and determining prognosis. How the results of this research will be used. This research will be used to i) identify men at increased risk of PrCa ii) determine if genetic susceptibility to PrCa can be used for targeted PrCa screening iii) determine how genetic susceptibility to PrCa can be used in PrCa care


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.4 POPULATION SCREENING
Health categories: CANCER AND NEOPLASMS